MXPA98006508A

MXPA98006508A - New compounds of cefem and pharmaceutical use of mis

Info

Publication number: MXPA98006508A
Application number: MXPA/A/1998/006508A
Authority: MX
Inventors: Sasaki Hiroshi; Takasugi Hisashi; Okuda Shinya; Yoshida Yoshiki; Matsuda Keiji
Original assignee: Fujisawa Pharmaceutical Co Ltd; Matsuda Keiji; Okuda Shinya; Sasaki Hiroshi; Takasugi Hisashi; Yoshida Yoshiki
Priority date: 1996-02-12
Filing date: 1998-08-12
Publication date: 1999-09-01

Abstract

The present invention relates to new cefem compounds, represented by the following general formula (I), wherein each symbol is as defined in the specification, or a salt thereof, which have antimicrobial activity against Helicobacter pylori, and useful as anti-Helicobacter pylori agents, anti-gastritis agents, anti-ulcer agents and anti-cancer agents

Description

NEW COMPOUNDS OF CEFEM AND PHARMACEUTICAL USE OF THE SAME * FIELD OF THE INVENTION _ This invention relates to new cefem compounds, and pharmaceutically acceptable salts thereof. More particularly, it relates to new cephem compounds and salts thereof, which have antimicrobial activity against Helicobacter pylori, to a pharmaceutical composition comprising the cephem compound or a pharmaceutically acceptable salt thereof, and to a method for prophylaxis and / or treatment of the ulcer, and the prophylaxis of stomach cancer in humans and animals.

TECHNICAL BACKGROUND Hitherto, inhibitors of acid secretion such as H2 blocker and proton pump inhibitor, and mucosal protective factor buffers have been used mainly for the treatment of peptic ulcers such as gastric ulcer and gastric ulcer. duodenal ulcer. While the use of the H blocker and the proton pump inhibitor shortens the treatment period, the problem of possible recurrence of the disease still remains unresolved. Helicobacter pylori (H. pylori) is a bacterium,. Gram negative found in the mucosal layer of the gastric epithelium of humans, and it has been found that infection with H. pylori induces gastrointestinal diseases, such as chronic gastritis and peptic ulcer (eg, gastric ulcer and duodenal ulcer) . There is a growing number of reports on the effectiveness of H. pylori eradication to treat intractable ulcers and the prevention of ulcer recurrence. The drug having an antimicrobial action on H. pylori is useful for the treatment and / or prevention of gastritis and ulcer, and a new drug having such pharmacological action is desired.

DESCRIPTION OF THE INVENTION An object of this invention is to provide new cephem compounds and salts thereof, which have antimicrobial activity against Helicobacter pylori.

The cephem compounds and salts thereof are useful as anti-Helicobacter pylori agents, anti-gastritis agents, anti-ulcer agents and anti-cancer agents. The cephem compounds and salts thereof can be used as anti-Helicobacter pylori agents, anti-gastritis agents, anti-ulcer agents and anti-cancer agents in combination with an acid secretion inhibitor, such as an H2 blocker. and a proton pump inhibitor. A further object of this invention is to provide a pharmaceutical composition for the prophylactic and / or therapeutic treatment of diseases caused by infection by Helicobacter pylori in humans or animals, comprising, as an active ingredient, the cephem compound or a pharmaceutically salt acceptable of it. A further object of this invention is to provide a therapeutic method for the prophylaxis and / or treatment of diseases caused by Helicobacter pylori infection, such as gastritis, ulcer [e.g., peptic ulcer (e.g., gastric ulcer, duodenal ulcer, anastomotic ulcer, etc.), etc.], MALT lymphoma, non-ulcer dyspepsia, and stomach cancer in humans and animals.

The cephem compounds in the present invention can be represented by the following general formula (I): wherein R1 is aryl (lower alkyl), which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl which can form a ring together with the carbon atom at which is attached lower alkyl, hydroxy and halogen; heterocyclyl (lower alkyl) which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and protected amino; or cyano (lower alkenyl thio) (lower alkyl); R is a heterocyclic group which has from 1 to 3 suitable substituent (s) selected from the group consisting of acyl (lower alkyl), hydroxy- (lower alkyl), mono or di (lower alkylamino) - (lower alkyl), amino (lower alkyl), protected amino (lower alkyl), acyl, acylamino and aryl having carboxy, in which the heterocyclic group may additionally have lower alkyl; pyridyl (lower alkyl); pyrazolylethyl, which may have aryl (lower alkyl); thiadiazolyl (lower alkyl); 5-aminothiazolyl; thiadiazolyl having lower alkyl; heterocyclyl (lower alkenyl) which may have from 1 to 3 suitable substituent (s); or heterocyclicthio (lower alkyl) which may have from 1 to 3 suitable substituent (s); and R3 is carboxy or protected carboxy, with the proviso that 1) when R1 is aryl (lower alkyl) and R2 is thiadiazolyl having lower alkyl, then R3 is acyloxy (lower alkoxycarbonyl), 2) when R1 is aryl (lower alkyl) ) having halogen, then R2 is not thiadiazolyl having lower alkyl, 3) when R- is aminothiazolyl (lower alkyl), then R 'is not thiadiazolyl having lower alkyl. • The cephem (I) compound or a salt thereof can be prepared by processes illustrated in the following reaction schemes. Process 1 (II) (i: or a salt thereof or a salt thereof Process 2 Elimination of (la) (Ib) or a salt thereof or a salt thereof Process 3 R -COOH (V) or its reactive derivative in the rut or carboxy or (IV) (I) or its reactive derivative or a salt thereof in the amino group or a salt thereof da) (Ib) or a salt thereof or its reactive derivative in the carboxy group or a salt thereof in which R1, R2 and R3 are each as defined above, R4 is a leaving group, and R5 is protected carboxy. The starting compounds (II) and (IV) or a salt thereof can be prepared by the processes illustrated in the following schemes. Process A Process B R -COOH (V) or its reactive derivative (V; or its reactive derivative or a sa (IlI) thereof in the amino group or a salt thereof Process C HS-R (III) (VI) (VIII) or a salt thereof or a salt thereof Process D Removal of the protecting group of the amino (VIII) (IV) or a salt thereof or a salt thereof in which R1, R2, R3 and R4 are each as defined above, and R is protected amino. Suitable examples of the various definitions of cephem (I) compounds of the present invention which are to be included within the scope of the invention, which are given in the description of the present application, are explained in detail in the following . The term "lower" is intended to mean a group having from 1 to 2 carbon atoms, preferably from 1 to 4 carbon atoms, unless otherwise provided. The "lower alkyl" suitable portion and "lower alkyl" in "aryl (lower alkyl)", "heterocyclyl (lower alkyl)" "acyl (lower alkyl)", "hydroxy (lower alkyl)", "mono or di (lower alkylamino) - (lower alkyl) "," amino- (lower alkyl) "," acylamino (lower alkyl) ", "phenyl (lower alkyl)", etc., may include straight or branched chain portions having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl, preferably those having 1 to 4 carbon atoms.

The suitable "halogen" may include chlorine, bromine, fluorine and iodine. The suitable "lower alkenyl" portion and "lower alkenyl" may include straight or branched chain alkenyl having from 2 to 6 carbon atoms, such as vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 1-pentenyl and 2-pentenyl, preferably the portions having from 2 to 4 carbon atoms. Suitable "lower alkylidene" may include straight or branched chain such as methylene, ethylidene, propylidene, vinylidene, butylidene, isopropylidene, pentylidene, t-butylidene, hexylidene, and the like, in which the preferred portions may be the alkylidene from 1 to 4 carbon atoms, and the most preferred may be propylidene. The "ring" suitable in "lower alkyl which can form a ring together with the carbon atom to which the lower alkyl is attached" can be cyclo (alkyl of 3 to 6 carbon atoms), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, in which the preferred one may be the cycloalkyl of 3 to 4 carbon atoms, and the most preferred one may be cyclopropyl.

The "aryl" portion suitable in "aryl (lower alkyl)" may include aryl of 6 to 10 carbon atoms, such as phenyl, naphthyl, tolyl, xylyl, mesityl and cumenyl, in which phenyl is most preferred. The preferred example of "aryl (lower alkyl)" may include mono or di or tri aryl (lower alkyl) such as benzyl, phenethyl, trityl, a-methylbenzyl and naphthylmethyl, in which phenyl (lower alkyl) is the most preferred. , and the most preferred is benzyl. The portion "lower alkyl" and "aryl" in "aryl (lower alkyl)" may each have 1 to 3 suitable substituent (s), such as lower alkyl, which may form a ring together with the atom of carbon to which the lower alkyl is attached, hydroxy, halogen, and the like. The "heterocyclyl" portion suitable in "(lower) heterocyclyl (lower alkyl)", "heterocyclic group", etc., may include a monocyclic or polycyclic, saturated or unsaturated heterocyclic group, containing at least one heteroatom such as an oxygen, sulfur, nitrogen, and the like, such as an unsaturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 membered) containing 1 to 4 nitrogen atom (s), eg, pyrrolyl, pyrrolinyl, imidazolyl , pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazole (for example, 4H-1, 2,4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, etc. ), tetrazolyl (for example, 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8 membered heterlic group (more preferably 5 or 6 membered containing from 1 to 4 nitrogen atom (s), for example, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, etc., unsaturated condensed heterlic group containing 1 to 4 nitrogen atom (s), for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc., 3 to 8 unsaturated heteromonlic group (more preferably 5 or 6 members) ) containing from 1 to 2 oxygen atom (s) and from 1 to 3 nitrogen atom (s), for example, oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1, 3, 4) -oxadiazolyl, 1, 2, 5-oxadiazolyl, etc.), etc. saturated 3 to 8 member heteromonlic group (more preferably 5 or 6 members) containing * 1 to 2 atom (s) of oxygen and 1 to 3 atom (s) of nitrogen, for example, morpholinyl, sidnonyl, etc.; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom (s) and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, etc .; 3 to 8 membered unsaturated heteromonocyclic group (more preferably 5 or 6 membered) containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example, thiazolyl, isothiazolyl, thiadiazolyl ( for example, 1,2,3-thiadiazolyl, 1, 2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; saturated 3 to 8 membered heteromonocyclic group (more preferably 5 or 6 membered containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), for example, thiazolidinyl, etc .; 3 to 8 membered unsaturated heteromonocyclic (more preferably 5 or 6 membered) containing from 1 to 2 sulfur atom (s), for example, thienyl, dihydrodithiinyl, dihydrodi thyl, etc., unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom (s) and from 1 to 3 nitrogen atom (s), for example, benzothiazolyl, "* benzothiadiazolyl, 4, 5, 6, 7-tetrahydrobenzothiazolyl, etc., 3 to 8 membered unsaturated heteromonocyclic group (more preferably 5 or 6 membered) containing an oxygen atom, eg, furyl, etc.; 3 to 8 membered unsaturated heteromonocyclic (more preferably 5 or 6 membered) containing an oxygen atom and 1 to 2 sulfur atom (s), eg, dihydrooxathiinyl, etc., unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom (s), for example, benzothienyl, benzodithiinyl, etc., unsaturated condensed heterocyclic group containing an oxygen atom and from 1 to 2 sulfur atom (s), for example, benzoxatinyl, etc .; and the like, the "lower alkyl" portion suitable in "heterocyclyl (lower alkyl)" can be referred to "lower alkyl" mentioned above, wherein alkyl of 1 to 4 carbon atoms may be preferred, and methyl may be the most preferred. Preferred examples of "heterocyclyl (lower alkyl)" for R1 may include the lower alkyl having an unsaturated 3 to 8 membered heteromonocyclic group containing from 1 to 2 sulfur atom (s), and lower alkyl having a heteromonocyclic group from 3 to 8 unsaturated members containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), the most preferred one being thienyl (alkyl of 1 to 4 carbon atoms), thiazolyl (alkyl of 1 to 4 carbon atoms), and thiadiazolyl (alkyl of 1 to 4 carbon atoms), and most preferred may be thienylmethyl, thiazolylmethyl and thiadiazolylmethyl. A preferred example of "heterocyclic group" for R 2 may include a 3 to 8 membered unsaturated heteromonocyclic group containing from 1 to 4 nitrogen atom (s), an unsaturated 3 to 8 membered heteromonocyclic group containing from 1 to 2 atom (s) of sulfur and from 1 to 3 nitrogen atom (s) and the unsaturated unsaturated heterocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), the most preferred ones can be thiadiazolyl, thiazolyl, triazolyl, tetrazolyl and tetrahydrobenzothiazolyl. The suitable "acyl" portion and "acyl" in "acyl (lower alkyl)", "acylamino (lower alkyl)" or "acylamino" may include carboxy, carbamoyl, thiocarbamoyl, or an aliphatic acyl group and acyl group containing a group aromatic, which is referred ^ as an aromatic acyl, or a heterocyclic ring, which is referred to as a heterocyclic acyl. Suitable examples of the acyl can be illustrated as follows: carboxy; carbamoyl; thiocarbamoyl; aliphatic acyl such as lower or higher alkanoyl (for example formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoilo, octadecanoilo, * nonadecanoilo, icosanoilo, etc.); lower or higher alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyl-oxycarbonyl, etc.); lower or higher alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (for example, methoxysulfonyl, ethoxysulfonyl, etc.); or similar; mono or di (lower alkyl) aminocarbonyl (for example, methylalkylcarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, diethylaminocarbonyl, N-methyl-N-ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl, N-ethyl-1-N-pro) laminocarbonyl, etc.); aromatic acyl such as aroyl (for example, benzoyl, toluoyl, naphthoyl, etc.); Ar (lower alkanoyl) [e.g., phenyl (lower alkanoyl) (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenyl isobutanoyl, phenyl pentanoyl, phenylhexanoyl, etc.], naphthyl (lower alkanoyl) (e.g. naphthylacetyl, naphthylpropanoyl, naphtl-butanoyl , etc.), etc.]; Ar (lower alkenoyl) [eg, phenyl (lower alkenoyl) (eg, phenylpropenoyl, phenyl-butenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (lower alkenoyl) (eg example, naphthylpropenoyl, naphthylbutenoyl, etc.), etc.]; Ar (lower alkoxycarbonyl) [eg, phenyl (lower alkoxycarbonyl) (for example benzyloxycarbonyl, etc.), etc.]; aryloxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl , etc.); aryloxy (lower alkanoyl) (for example, phenoxyacetyl, phenoxypropionyl, etc.); arylcarba oyl (e.g., phenylcarba oyl, etc.); arylthiocarbamoyl (for example, phenylthiocarbamoyl, etc.); arylglyoxyloyl (for example, phenylglyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or similar; heterocyclic acyl such as heterocyclylcarbonyl; heterocyclyl (lower alkanoyl) (for example, heterocyclylacetyl, heterocyclylpropanoyl, hetero-cyclylbutanoyl, heterocyclylpentanoyl, heterocyclyl-hexanoyl, etc.); heterocyclyl (lower alkenoyl) (for example, tert-cyclicpropenoyl, heterocyclylbutenoyl, hetero-cyclylpentenoyl, heterocyclylhexanoyl, etc.); heterocyclyl glyoxyloyl; heterocyclyl (lower alkylcarbamoyl) (for example, heterocyclylmethylcarbamoyl, heterocyclyl-ethylcarbamoyl, heterocyclylpropylcarbamoyl, hetero-cyclylhexylcarbamoyl, etc.); or similar; wherein the "heterocyclyl" portion suitable in the terms "heterocyclylcarbonyl", "heterocyclyl- (lower alkanoyl), heterocyclyl (lower alkenoyl)" and "heterocyclylglyoxyloyl" may be referred to the "heterocyclyl" portion mentioned above. Suitable "lower cyano (lower alkyl) (lower alkyl)" may include cyanovinylthiomethyl, cyanovinylthioethyl, cyanovinylthiopropyl, 3-cyano-1-propenylthiomethyl, 3-cyano-1-propenyl thioethyl, cyanoalylthiomethyl and cyanoalylthioethyl, in which the most preferred may be it is the cyano (alkenylthio of 2 to 4 carbon atoms) (alkyl of the ß carbon atoms), and the most preferred one can be cyanovinylthiomethyl. The "lower alkyl" portion suitable in "acyl (lower alkyl)" can be referred to the "lower alkyl" mentioned above, in which the preferred one is alkyl of 1 to 4 carbon atoms, and the most preferred one can be methyl and ethyl. The "acyl" portion suitable in "acyl- (lower alkyl)" can be referred to the "acyl" mentioned above, in which the preferred one can be carboxy, carbamoyl, mono or di (lower alkylaminocarbonyl), lower alkoxycarbonyl, N-heterocyclylcarbonyl , N-heterocyclyl- (lower alkylcarbamoyl) and thiocarbamoyl, and the most preferred may be carboxy, carbamoyl, dimethylaminocarbonyl, ethoxycarbonyl, methoxycarbonyl, morpholinocarbonyl, N-methylcarbamoyl, N-pyridyl-methylcarbamoyl and thiocarbamoyl. A preferred example of "acyl (lower alkyl)" may include acyl (C 1 -C 4) alkyl, and the most preferred may be carboxymethyl, carboxyethyl, carboxypropyl, carboxyisopropyl, carboxybutyl, carboxy-t-butyl, carbamoylmethyl, carbamoylethyl , carbamoylpropyl, carbamoilisopropilo, carbamoylbutyl, carbamoyl-t-butyl, methylaminocarbonylmethyl, dimetilaminocarbonil- ethyl, et ilaminocarbonilmet yl, diethylaminocarbonyl-ethyl propilaminocarboniletilo, butylaminocarbonyl-propyl, ethoxycarbonylmethyl, folinocarbonilmetilo mor, piridilmetilcarbamoilmetilo, methoxycarbonylethyl and tiocarbamoilmetilo, and most preferred can be carboxymethyl, carbamoylmethyl, dimethylaminocarbonylmethyl, ethoxycarbonylmethyl, mor folinocarbonylmethyl, pyridylmethylcarbamoylmethyl, methoxycarbonylethyl and thiocarbamoylmethyl. 1 * The "lower alkyl" portion suitable in "hydroxy (lower alkyl)" can be referred to "lower alkyl" mentioned above, wherein alkyl of 1 to 4 carbon atoms may be preferred, and methyl and ethyl may be most preferred. The preferred example of "hydroxy (lower alkyl)" may include hydroxy (alkyl of 1 to 4 carbon atoms), and most preferred may be hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and hydroxy-t-butyl, and Hydroxymethyl and hydroxyethyl are the most preferred. The "lower alkyl" portion suitable in "Mono or di (lower alkylamino) (lower alkyl)" can be referred to the "lower alkyl" mentioned above, in which the preferred one can be methyl. The "mono or lower dialkylamino" portion suitable in "mono or lower dialkylamino (lower alkyl)" may include methylamino, ethylamino, propylamino, isopropylamino, butylamino, tert-butylamino, isobutylamino, pentylnoxy, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, diisopropylamino, dipentylamino, dihexylamino and N-methyl-N-ethylamino, in which the preferred one may be mono or di (C 1 -C 4 alkylamino), and the most preferred one may be dimethylamino. The preferred example of "mono- or di (lower alkylamino) (lower alkyl)" may include mono- or di- (C 1-4 alkylamino) (C 1-4 -alkyl), and the most preferred may be the methylaminomethyl, ethylaminoethyl, propylaminomethyl, isopropylaminopropyl, butylaminomethyl, tert-butyl-aminoethyl, isobutylaminobutyl, dimethylaminomethyl, diethylaminoethyl, dipropyl, inomethyl, dibutylamino-propyl, diisopropylaminobutyl, and N-methyl-N-ethylamino-methyl, and dimethylamino is most preferred. - ethyl. The "lower alkyl" portion suitable in "amino (lower alkyl)" can be referred to the "lower alkyl" mentioned above, in which the preferred one can be "alkyl of 1 to 4 carbon atoms", and the most preferred one can be be methyl The preferred example of "amino (lower alkyl)" may include amino (alkyl of 1 to 4 carbon atoms), the most preferred may be aminomethyl, aminoethyl, aminopropyl, aminoisopropyl, aminobutyl and amino-t-butyl, and the most preferred may be aminomethyl.

The "lower alkyl" portion suitable for "amino (lower alkyl) protected" for R 2 may be referred to the "lower alkyl" mentioned above, in which the preferred one may be alkyl (1-4 carbon atoms), and the most preferred may be methyl. The "protected amino" portion suitable in "protected (lower) alkyl" may include an acylamino. The appropriate "acyl" portion in the "acylamino" mentioned above may be referred to the "acyl" mentioned above, in which the preferred one may be the lower alkoxycarbonyl, and the most preferred may be the alkoxycarbonyl of 1 to 4 'carbon atoms, and the most preferred one may be the t-butoxycarbonyl. The preferred example of "acylamino (lower alkyl)" may include lower alkoxycarbonylamino (lower alkyl), the most preferred may be alkoxycarbonylamino of 1 to 4 carbon atoms (alkyl of 1 to 4 carbon atoms), and the most preferred may be t-butoxycarbonylaminomethyl. The "acyl" portion suitable in "acylamino" can be referred to the "acyl" mentioned above, in which the preferred one can include carbamoyl or lower alkanoyl, and the most preferred one can be carbamoyl, formyl and acetyl. The preferred example of "acylamino" 'may include ureido and lower alkanoylamino, in which the preferred one may be ureido and (C 1 -C 4 alkanoylamino), and the most preferred may be ureido, formulamino and acetylamino. Suitable "carboxyl-containing aryl" may include carboxyphenyl, carboxy naphyl, carboxyantrile, and the like, in which the most preferred may be carboxyphenyl. The "suitable pyridyl (lower alkyl)" may include pyridylmethyl, pyridylethyl, pyridylpropyl, pyridylbutyl, pyridylpentyl, pyridylhexyl, and the like, in which the preferred one may be pyridyl (C 1 -C 4) alkyl, and the most preferred one may be pyridylmethyl and pyridylethyl. The suitable "thiadiazolyl (lower alkyl)" may include thiadiazolylmethyl, thiadiazolylethyl, thiadiazolylpropyl, thiadiazolylbutyl, thiadiazolyl-pentyl, thiadiazolylhexyl, and the like, in which the thiadiazolyl (alkyl of 1 to 4 carbon atoms) may be preferred, and the more preferred may be 1,2,3-thiadiazolylmethyl.

The "heterocyclyl" portion suitable in "heterocyclyl (lower alkenyl)" can be referred to the "heterocyclyl" portion mentioned above, wherein the preferred one can be an unsaturated 3 to 8 member heteromonocyclic group containing from 1 to 4 atom (s) of nitrogen, and the most preferred may be pyridyl and pyrazolyl. The "lower alkenyl" portion suitable in "heterocyclyl (lower alkenyl)" can be referred to the "lower alkenyl" portion mentioned above, in which the preferred one can be alkenyl of 2 to 4 carbon atoms, and the most preferred one It can be vinyl. The preferred "heterocyclyl (lower alkenyl)" portion may include (2 to 4 carbon atoms alkenyl) having an unsaturated 3 to 8 membered heteromonocyclic group, containing from 1 to 4 nitrogen atom (s), in which the preferred one may be pyridylvinyl and pyrazolylvinyl. The "right substituent" suitable in "heterocyclyl (lower alkenyl), which may have from 1 to 3 suitable substituent (s)" may include the "acyl" mentioned above, in which the preferred one may be aryl (lower alkylcarbonyl), and the more preferred may be phenyl (1 to 4 carbon atoms), and benzylcarbonyl may be the most preferred. The "heterocyclyl" portion suitable in "heterocyclylthio (lower alkyl), which may have from 1 to 3 suitable substituent (s)" may be referred to the "heterocyclyl" portion mentioned above, wherein the Preferred may be a 3- to 8-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), and thiazolyl may be most preferred. The preferred "heterocyclylthio (lower alkyl)" portion may include thio (C 1-4) alkyl having an unsaturated 3 to 8 membered heteromonocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 atom (s) of nitrogen, in which the thiazolyl thiomethyl may be the preferred one. Suitable "suitable substituents" on "heterocyclicthio (lower alkyl) which may have from 1 to 3 suitable substituent (s)" may include the "acyl (lower alkyl)" mentioned above, in which may be carbamoyl (alkyl of 1 to 4 carbon atoms), and most preferred may be carbamoylmethyl.

The suitable "protected carboxy" may include the carboxy group protected by a conventional protecting group such as an esterified carboxy group, and the like, and the specific examples may be substituted or unsubstituted lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, 2- (dimethylamino) ethoxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl), unsubstituted or substituted aryloxycarbonyl (e.g., phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2- naphthyloxycarbonyl), and substituted or unsubstituted aryl (lower alkoxycarbonyl), for example, mono or di or triphenyl (lower alkoxycarbonyl), which may be substituted with nitro (for example, benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl), acyloxy (lower alkoxycarbonyl) (for example t-butylcarbonyloxymethyl and carbonyl, 1-t-butylcarbonyl-oxy-1-methylmethyloxycarbonyl, 1-isopropylcarbonyloxy-1- ethemethyloxycarbonyl, 1-isobutylcarbonyloxy-1-methyl-methyloxycarbonyl). The suitable "leaving group" can include a substituted lower alkoxy such as lower alkoxy (lower alkoxy) (for example methoxymethoxy), lower alkoxy (lower alkoxy) (lower alkoxy) (for example methoxyethoxymethoxy), a substituted aryl (lower alkoxy) or unsubstituted (for example, benzyloxy, nitrobenzyloxy); acyloxy such as lower alkanoyloxy, (for example acetoxy, propionyloxy, pivaloyloxy), aroyloxy (for example, benzoyloxy, fluorencarbonyloxy), lower alkoxycarbonyloxy (for example, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, isopropoxycarbonyloxy, butoxycarbonyloxy, isobutoxycarbonyloxy, tert-butoxycarbonyloxy, pentyloxy- carbonyloxy, hexyloxycarbonyloxy), a substituted or unsubstituted aryl (alkoxycarbonyloxy) (for example, benzyloxycarbonyloxy, bromobenzyloxycarbonyloxy), arenesulphonyloxy (for example benzenesulfonyloxy, tosyloxy), alkanesulphonyloxy, which may have one or more of them (s) suitable (eg, methanesulfonyloxy, trifluoromethanesulfonyloxy, ethanesulfonyloxy); and tri (lower alkylsilyloxy) (for example trimethylsilyloxy). The suitable "protected amino" may include an acylamino group or an amino group substituted by a conventional protecting group such as Ar (lower alkyl) which may have suitable substituent (s) (for example benzyl, trityl, etc.) and similar. fa- The appropriate "acyl" portion in the "acylamino" mentioned above may be referred to the "acyl" mentioned above, in which the preferred one may be the lower alkanoyl, and the most preferred may be formyl and acetyl. The preferred "protected amino" may include acylamino, in which the preferred one may be the lower alkanoylamino, and the most preferred may be the formylamino and the acetylamino. Suitable salts of the subject compound (I) are pharmaceutically acceptable salts such as conventional non-toxic salts, and include the organic acid addition salts (eg, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p- toluene sulfonate), an inorganic acid addition salt (for example hydrochloride, bromohydrate, sulfate, phosphate), an alkali metal salt (for example sodium salt, potassium salt) and an alkaline earth metal salt (for example calcium salt, magnesium salt). Suitable examples of the salts of compounds (II), (III), (IV), (V), (VI), (VII) and (VIII) in Processes 1 to 4 and in Processes A to D are going to be referred to those exemplified for the object compound (I).

Particularly, preferred examples of the compound (I) in the present invention are as follows: the compound (I), wherein R 1 is aryl (lower alkyl), which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl which can form a ring together with the carbon atom to which the lower alkyl, hydroxy and halogen are attached; - lower alkyl having a 3- to 8-membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atom (s), which may have from 1 to 3 its appropriate constituent (s) selected from the group which consists of lower alkenyl, lower alkylidene, halogen, amino and acylamino; o-cyano (lower alkenylthio) (lower alkyl); R2 is an unsaturated heteromonocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), which has 1 to 3 suitable substituent (s) selected from the group a group consisting of acyl (lower alkyl), hydroxy (lower alkyl), mono or di (lower alkylamino) - (lower alkyl), amino (lower alkyl), acylamino- (lower alkyl), acyl, acylamino and aryl having carboxy , in which the heterocyclic monocyclic group may additionally have a lower alkyl; -pyridyl (lower alkyl); -pyrazolylethyl, which may have aryl (lower alkyl); -thiadiazolyl (lower alkyl); -5-aminothiazolyl; -thiadiazolyl having lower alkyl; 3 to 8 membered unsaturated heteromonocyclic group containing 1 to 4 nitrogen atom (s), which has acyl (lower alkyl); lower alkenyl having a 3- to 8-membered unsaturated heteromonocyclic group containing from 1 to 4 nitrogen atom (s) which may have acyl; or - lower alkylthio having a 3 to 8 membered unsaturated heteromonocyclic group containing 1 to 2 sulfur atom (s) and 1 to 3 nitrogen atom (s), which may have acyl (lower alkyl); and R3 is protected carboxy or carboxy, with the proviso that 1) when R1 is aryl (lower alkyl) and R ^ is thiadiazolyl having lower alkyl, then R3 is acyloxy (lower alkoxycarbonyl), 2) when R1 is aryl (alkyl) lower) having halogen, then R2 is not thiadiazolyl having, lower alkyl, 3) when R1 is aminothiazolyl (lower alkyl), then R2 is not thiadiazolyl having lower alkyl, the most preferred being compound (I), wherein R "1 is phenyl (lower alkyl), which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, which may form a 3 to 7-membered ring together with the carbon atom to which the lower alkyl *, hydroxy and halogen is attached; -thienyl (lower alkyl), thiazolyl (lower alkyl) or thiadiazolyl (lower alkyl), each of which may have 1 to 3 substituent ( s) adequate (s) selected from the group consisting of of lower alkenyl, lower alkylidene, halogen, amino and acylamino; o-cyano (lower alkenylthio) (lower alkyl); R2 is thiazolyl, which has from 1 to 3 its appropriate constituent (s) selected from the group consisting of acyl (lower alkyl), hydroxy (alkyl) ^ 8-lower), acyl, acylamino and phenyl having carboxy, in which the thiazolyl may additionally have a lower alkyl; -thiadiazolyl, which has from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, hydroxy (lower alkyl), mono or di (lower alkylamino) (lower alkyl) and amino ( lower alkyl); -pyridyl (lower alkyl); -pyrazolylethyl, which may have trityl; -thiadiazolyl (lower alkyl); -5-aminothiazolyl; -5-methy1-1, 3,4-thiadiazolyl; -triazolyl, which has acyl (lower alkyl); -tetrazolyl, which has acyl (lower alkyl); lower alkenyl having a 3- to 8-membered unsaturated heteromonocyclic group containing from 1 to 4 nitrogen atom (s), which may have acyl; or - lower alkylthio having an unsaturated heteromonocyclic group containing from 1 to 2 sulfur atom (s) and from 1 to 3 nitrogen atom (s), which may have acyl (lower alkyl); and R3 is carboxy or carboxy protected; much more preferred is compound (I), wherein R1 is phenyl (lower alkyl), thienyl (lower alkyl), thiazolyl (lower alkyl) or thiadiazolyl- (lower alkyl), R 'is thiazolyl, which has a suitable substituent selected from the group consisting of carboxy (lower alkyl), carbamoyl (lower alkyl), mono or di-alkylaminocarbonyl lower (lower alkyl), hydroxy (lower alkyl), carbamoyl, morpholinocarbonyl (lower alkyl), pyridyl (lower alkylaminocarbonyl) - ( lower alkyl), lower alkoxycarbonyl- (lower alkyl), thiocarbamoyl (lower alkyl), ureido and phenyl having carboxy, in which the thiazolyl may additionally have a lower alkyl; thiadiazolyl, which has a suitable substituent selected from the group consisting of hydroxy (lower alkyl), di (lower alkylamino) (lower alkyl), amino (lower alkyl), lower alkoxycarbonylamino (lower alkyl) and carboxy (lower alkyl); -pyridyl (lower alkyl); -pyrazolylethyl, which may have trityl; -thiadiazolyl (lower alkyl); -5-aminothiazolyl; -5-methyl-1,3,4,4-thiadiazolyl; -triazolyl, which has a suitable substituent, selected from the group consisting of carboxy (lower alkyl) and lower alkoxycarbonyl (lower alkyl); -tetrazolyl, which has a carboxy (lower alkyl); pyridyl (lower alkenyl); o -pyrazolyl (lower alkenyl), which has a benzylcarbonyl; and R3 is carboxy or carboxy protected; one of the still much more preferred is compound "(I), wherein R1 is phenyl (lower alkyl), R2 is thiazolyl, which has a suitable substituent selected from the group consisting of carboxy (lower alkyl), carbamoyl (alkyl) lower), mono or di-alkylaminocarbonyl lower (lower alkyl), hydroxy (lower alkyl), carbamoyl, morpholinocarbonyl (lower alkyl), pyridyl (lower alkylaminocarbonyl) (lower alkyl), lower alkoxycarbonyl (lower alkyl), thiocarbamoyl (lower alkyl) , ureido and phenyl having carboxy, wherein the thiazolyl may additionally have lower alkyl; -thiadiazolyl, which has a suitable substituent selected from the group consisting of hydroxy (lower alkyl), di (lower alkylamino) (lower alkyl), amino (lower alkyl), lower alkoxycarbonylamino (lower alkyl) and carboxy (lower alkyl); -pyridyl (lower alkyl); -pyrazolylethyl, which may have trityl -thiadiazolyl (lower alkyl); - 5-aminothiazolyl; -5-methyl-1,3,4,4-thiadiazolyl; -triazolyl, which has a suitable substituent selected from the group consisting of carboxy (lower alkyl) and lower alkoxycarbonyl (lower alkyl); -tetrazolyl, which has a carboxy (lower alkyl); pyridyl (lower alkenyl); o -pyrazolyl (lower alkenyl), which has a benzylcarbonyl; and RJ is carboxy, another of the still much more preferred is compound (I), wherein R1 is thienyl (lower alkyl), R2 is thiazolyl, which has a suitable substituent selected from the group consisting of carboxy (lower alkyl) and carbamoyl (lower alkyl), or thiadiazolyl having hydroxy (lower alkyl), and R3 is carboxy, an extremely preferred one is compound (I), wherein R1 is phenyl (lower alkyl), R2 is thiazolyl having carboxy (alkyl) lower) or thiazolyl having carbamoyl (lower alkyl), and R3 is carboxy, an extremely more preferred one is compound (I), wherein R1 is thienyl (lower alkyl), R2 is thiazolyl having carboxy (lower alkyl) or thiazolyl having carbamoyl (lower alkyl), and R3 is carboxy, the most preferred is compound (I), wherein R1 is phenyl (lower alkyl), R2 is thiazolyl having carbamoyl (lower alkyl), and R3 is carboxy, another more preferred is compound (I), wherein R1 is thienyl (lower alkyl), R2 is thiazolyl having carbamoyl (lower alkyl), and RJ is carboxy. The processes for preparing the cephem compound (I) or a salt thereof in the present invention are explained in detail in the following.

Process 1 The compound (I) or a salt thereof can be prepared by reacting the compound (I) or a salt thereof with the compound (III) or a salt thereof. Suitable salts of the compound (III) include alkali metal salts (eg, sodium salt, potassium salt). The reaction is usually carried out in the presence of a base. Suitable examples of the base include organic bases such as triethylamine, trimethylamine, N, N-diisopropylethylamine, dimethylamine, N-methylmorpholine and pyridine, and inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), and alkali metal hydrogen carbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate). The reaction is usually carried out in a solvent such as water, acetone, acetonitrile, dioxane, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, 1,2-dimethoxyethane, a mixture thereof or any other solvent that does not influence in a adversely affect the reaction The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2 The object compound (Ib) or a salt thereof can be prepared by subjecting the compound (Ia) or a salt thereof to a removal reaction of the carboxy protecting group. In the present elimination reaction, all conventional methods used for the removal of the carboxy protecting group, for example, hydrolysis, reduction, elimination using a Lewis acid, etc. are applicable. When the carboxy protecting group is an ester, it can be removed by hydrolysis or elimination using a Lewis acid. Hydrolysis 1 * is preferably carried out in the presence of a base or an acid. Suitable bases include, for example, inorganic bases such as alkali metal hydroxides (e.g. sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g. magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g. example, sodium carbonate, potassium carbonate), ferrous alkali metal carbonates (eg magnesium carbonate, calcium carbonate), alkali metal hydrogen carbonates (eg sodium hydrogen carbonate, potassium hydrogen carbonate), metal acetates alkaline (e.g., sodium acetate, potassium acetate), ferrous alkali metal phosphates (e.g. magnesium phosphate, calcium phosphate), and alkali metal hydrogen phosphates (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate); and organic bases such as trialkylamines (for example trimethylamine, triethylamine), picoline, N-methylpyrrolidine, N-methylmorpholine, and 1,5-diazabicyclo [4.3.0] non-5-one, 1,4-diazabicyclo [2.2.2] octane, and 1,5-diazabicyclo [5.4.0] undecen-5. Hydrolysis using a base is often carried out in water or a solvent * hydrophilic organic% or a mixed solvent thereof. Suitable acids include organic acids (for example formic acid, acetic acid, propionic acid) and inorganic acids (for example hydrochloric acid, hydrobromic acid, sulfuric acid). The present hydrolysis is usually carried out in water or an organic solvent or a mixed solvent thereof. The reaction temperature is not critical, and can be selected appropriately according to the kind of carboxy protecting group and the elimination method. The elimination using a Lewis acid is "preferable to remove a substituted or unsubstituted aryl (lower alkyl) ester., and is carried out by reacting the compound (Ia) or a salt thereof with a Lewis acid. Examples of the Lewis acid are boron trihalides (for example boron trichloride, boron trifluoride), titanium tetrahalides (for example titanium tetrachloride, titanium tetrabromide), tin tetrahalides (for example tin tetrachloride, tetrabromide tin), aluminum halides (for example aluminum chloride, aluminum bromide), and trihaloacetic acids (for example trichloroacetic acid, trifluoroacetic acid). This elimination reaction is preferably carried out in the presence of cation trapping agents (eg anisole, phenol) and is usually carried out in a solvent such as a nitroalkane (eg nitromethane, nitroethane), an alkylene halide (eg - example methylene chloride, ethylene chloride), diethyl ether, carbon disulfide or any other solvent that does not adversely influence the reaction. These solvents can be used alone or by mixing them with one another. The elimination reduction can preferably be conducted to remove a protecting group such as halo (lower alkyl) (for example 2-iodoethyl, 2, 2, 2-trichloroethyl) ester, and aryl (lower alkyl) (for example benzyl ester). The reduction applicable for the elimination reaction includes reduction using a combination of a metal (for example zinc, zinc amalgam) or a salt of a chromium compound (for example chromic chloride, chromic acetate) and an organic or inorganic acid ( for example, acetic acid, propionic acid, hydrochloric acid); and conventional catalytic reduction in the presence of a conventional metallic catalyst (e.g., palladium on carbon, Raney nickel). The reaction temperature is not critical, and the reaction is usually carried out under cooling, at room temperature or under heating.

Process 3 The compound (I) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative in the amino group or a salt thereof with the compound (V) or its reactive derivative in the carboxy group or a salt of it. Suitable reactive derivatives in the carboxy group of the compound (V) include an acid halide, an acid anhydride, an activated amide or an activated ester. Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed anhydride of acid with an acid such as substituted phosphoric acid (eg dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, sulphonic acid (e.g. methanesulfonic acid), aliphatic carboxylic acid (e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid), or an aromatic carboxylic acid (e.g. benzoic); an acid symmetric anhydride; an amide activated with imidazole, imidazole substituted at the 4-position, dimethylpyrazole, triazole or tetrazole; an activated ester (for example a cyanomethyl ester, methoxymethyl ester, a dimethyl-iminomethyl ester [(CH3) 2N + = CH-], vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenic ester, trichlorophene ester ionic, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenyl thioester, p-nitrophenol thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester) or an ester with a compound of N-hydroxy (for example N, -dimethylhydroxylamine, l-hydroxy-2- (lH) -pyridone, N-hydroxysuccinimide, N-hydroxy-phthalimide, 1-hydroxy-lH-benzotriazole). These reactive derivatives can optionally be selected from them according to the class of the compound (V) to be used. Suitable salts of the compound (V) and its reactive derivative include a basic salt such as an alkali metal salt (e.g., sodium salt, potassium salt), an alkaline earth metal salt (e.g. magnesium), an ammonium salt and an organic basic salt (for example, trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt). The suitable reactive derivative in the amino group of the compound (IV) includes the Schiff base type imino or its tautomeric enamine type isomer, formed by the reaction of the compound (IV) with a carbonyl compound such as an aldehyde or a ketone; a silyl derivative formed by the reaction of the compound (IV) with a silyl compound such as "bis (trimethylsilyl) acetamide, mono (trimethylsilyl) -acetamide or bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide or bis (trimethylsilyl) urea, and a derivative formed by the reaction of the compound (IV) with phosphorus trichloride or phosgene The reaction is usually carried out in a solvent such as water, an alcohol (for example methanol, ethanol), acetone , dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other solvent that does not adversely influence the reaction. This conventional solvent can also be used in a mixture with water. In this reaction, when the compound (V) is used in free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-dicyclohexyl carbodiimide; N-cyclohexyl-N '-morpholinoethylcarbodiimide; N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N '-di-isopropylcarbodiimide; N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide; N, N '-carboni Ibis- (2-methylimidazole); pentamethyleneethen-N-cyclohexine; diphenyl-N-cyclohexylimine; etoxiacet ileum; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; Isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; phosphorylazide phosphate; thionyl chloride; oxalyl chloride; lower alkyl haloformate (for example ethyl chloroformate, isopropyl chloroformate); fine tri-phenylphos; Get ouf of 2-ethyl-7-hydroxybenzisoxazolium; intramolecular salt of 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide; 1- (p-chlorobenzenesulphonyloxy) - ß-chloro-1 H-benzotriazole); or the so-called Vilsmeier reagent, prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride or oxalyl chloride. The reaction can also be carried out in the presence of an inorganic or organic base such as an alkali metal hydrogen carbonate, tri (lower alkylamine), pyridine, N- (lower alkylmorpholine) or N, N-di (lower alkylbeamine). The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 4 The object compound (s) or a salt thereof can be prepared by subjecting the compound (Ib) or a salt thereof to a carboxy protection reaction. This reaction can be carried out according to a conventional manner such as those described in the Examples or similar manners thereto. The processes for preparing the starting compounds (II) and (IV) or a salt thereof are explained in detail in the following.

Process A The compound (VII) or a salt thereof can be prepared by subjecting the compound (VI) or a salt thereof to a removal of the amino protecting group in the presence of an acid. Suitable acids include an organic acid (for example formic acid, acetic acid, propionic acid) and an inorganic acid (for example hydrochloric acid, hydrobromic acid, sulfuric acid). The reaction is usually carried out in a solvent such as water, an alcohol (for example methanol, ethanol), methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, a mixture thereof or any other solvent that does not adversely influence the reaction. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process B The compound (II) or a salt thereof can be prepared by reacting the compound (VII) or its reactive derivative in the amino group or a salt thereof with the compound (V) or its reactive derivative in the carboxy group or a salt of it.

This reaction can be carried out in substantially the same manner as in Process 3, and therefore the reaction mode and the reaction conditions (for example, the reactive derivatives, the condensing agents, the solvent, the reaction temperature ) of this reaction will be referred to those explained in Process 3.

Process C The compound (VIII) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (III) or a salt thereof. This reaction can be carried out in substantially the same manner as in Process 1, and therefore the reaction mode and the reaction conditions (eg, the bases, the solvent, the reaction temperature) of this reaction go to be referred to those explained in Process 1.

Process D The compound (IV) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to removal of the amino protecting group in the presence of an acid.

This reaction can be carried out in substantially the same manner as in Process A, and therefore the reaction mode and the reaction conditions (e.g., acids, solvent, reaction temperature) of this reaction are to be referred to those explained in Process A. The starting compound (VI) can be prepared by the known method, such as that described in Japanese Patent Publication No. 52-83492. The compounds obtained by the above processes can be isolated and purified by a conventional method, such as spraying, recrystallization, column chromatography or reprecipitation. It will be noted that each of the subject compounds (I) may include one or more stereoisomers, such as optical isomers and geometric isomers due to asymmetric carbon atoms or double bonds, and all of these isomers and mixtures thereof are included within the scope of the invention. scope of this invention. The cephem (I) compound and a pharmaceutically acceptable salt thereof include a solvate [e.g., inclusion compounds (e.g., hydrate, etc.)].

* * * The cephem (I) compound and a pharmaceutically acceptable salt thereof include both its crystalline form and its non-crystalline form. The cephem (I) compound and a pharmaceutically acceptable salt thereof are stable even in a strong acid such as gastric juice. The cephem (I) compound or a pharmaceutically acceptable salt thereof possesses antimicrobial activity against H. pylori, and are useful for the prophylaxis and / or treatment of gastritis, ulcer (e.g., gastric ulcer, duodenal ulcer, anas tomotic ulcer) ), malformation of MALT and non-ulcer dyspepsia, and prophylaxis of stomach cancer. The cephem (I) compound or a pharmaceutically acceptable salt thereof can be administered in combination with an acid secretion inhibitor such as an H2 blocker (for example cimetidine, ranitidine, famotidine, etc.) or a pump inhibitor. of protons (for example omeprazole, lansoprazole, etc.) for the prophylaxis and / or treatment of chronic gastritis, peptic ulcer (eg gastric ulcer, duodenal ulcer, anas tomotic ulcer), MALT lymphoma and non-ulcer dyspepsia, and prophylaxis of stomach cancer.

The cephem (I) compound or a pharmaceutically acceptable salt thereof is particularly effective for the prophylaxis- and / or treatment of diseases caused by Helicobacter pylori infection, such as gastritis, ulcer [e.g. peptic ulcer (e.g. ulcer gastric, duodenal ulcer, anastomotic ulcer, etc.), MALT lymphoma, non-ulcer dyspepsia, and stomach cancer, when administered with an acid secretion inhibitor such as an H2 blocker (eg, cimetidine, ranitidine, famotidine, etc.) or a proton pump inhibitor (eg omeprazole, lansoprazole, etc.). Particularly, since the cephem (I) compound or a pharmaceutically acceptable salt thereof possesses selective antimicrobial activity against H. pylori, it can selectively act on H. pylori without exerting an adverse influence on other useful enterobacteria. Accordingly, the cephem (I) compound or the pharmaceutically acceptable salts thereof serve very well for the eradication of H. pylori, and are useful for the treatment of ulcers and / or the prevention of recurrence of ulcers. The cephem (I) compound or a pharmaceutically acceptable salt thereof can be administered in combination with an acid secretion inhibitor such as an H2 blocker (for example cimetidine, ranitidine, famotidine, etc.) or a pump inhibitor. of protons (for example omeprazole, lansoprazole, etc.) for the treatment of ulcers and / or the prevention of recurrence of ulcers. For therapeutic purposes, the cephem (I) compound or a pharmaceutically acceptable salt thereof of the present invention can be used as such, or in the form of pharmaceutical preparations containing one of the compounds as an active ingredient in admixture with a pharmaceutically carrier. acceptable, such as a solid or liquid excipient, organic or inorganic, suitable for oral or parenteral administration. The pharmaceutical preparations can be capsules, tablets, dragees, granules, solutions, suspensions or emulsions. If desired, auxiliary substances, stabilizing agents, wetting agents or emulsifiers, buffers and other commonly used additives such as lactose, sialic acid, magnesium stearate, terry alba, sucrose, corn starch, talc, etc. may be included in these preparations. gelatin, agar, pectin, peanut oil, olive oil, cocoa butter and ethylene glycol.

While the dosage of the compound (I) will vary depending on the age and condition of the patient, an average individual dose of about 0.1 mg, 1 mg, 10 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg of the compound (I) may be effective in treating the ulcer. In general, amounts between 0.1 mg / person and about 2 can be administered per day, 000 mg / person. When the compound (I) is used in combination with an acid secretion inhibitor, a weight ratio of the compound (I) to an acid secretion inhibitor is in the following range: compound (I) / acid secretion inhibitor = 0.01 / 1 - 100/1 A preferred range is: compound (I) / acid secretion inhibitor = 1/1 -100/1 A more preferred range is: compound (I) / acid secretion inhibitor = 2.5 / 1-50/1 Another preferred range is: compound (I) / acid secretion inhibitor = 0.1 / 1 -10 / 1 According to the present invention, the following is provided: (1) A product comprising the compound of cephem (I) or a pharmaceutically acceptable salt thereof, and an acid secretion inhibitor, as a combined preparation for simultaneous, separate or sequential use for the prevention and / or treatment of diseases caused by Helicobacter pylori infection. (2) The cephem compound (I) or a pharmaceutically acceptable salt thereof, for the adjuvant therapy of diseases caused by Helicobacter pylori infection, with an acid secretion inhibitor. (3) The use of the cephem compound (I) or a pharmaceutically acceptable salt thereof, and an acid secretion inhibitor, for the manufacture of a medicament for simultaneous, separate or sequential use for the prevention and / or treatment of the disease caused by the infection by Helicobacter pylori. (4) A product comprising the cephem compound (I) and an acid secretion inhibitor for simultaneous, separate or sequential use as a medicament. (5) A pharmaceutical composition, comprising the cephem compound (I) and an acid secretion inhibitor, and optionally pharmaceutically acceptable carriers or excipients. ta- 5ß (ß) A pharmaceutical composition, characterized in that the composition is adapted only for oral administration and comprises, as an active ingredient, the cephem compound (I) or a pharmaceutically acceptable salt thereof, and an acid secretion inhibitor. (7) A product comprising: a) the cephem compound (I) or a pharmaceutically acceptable salt thereof, and b) an acid secretion inhibitor in a weight ratio of: a) ab) from 0.01 / 1 to 100 /1. (8) A method for the treatment of the inhibition of diseases caused by infection by Helicobacter pylori, which comprises administering an effective amount of the cephem (I) compound to a patient in need of such inhibition treatment. (9) The method of paragraph (8) above, wherein the cephem (I) compound is administered to such a patient in combination with an acid secretion inhibitor, in a weight ratio of the cephem compound (I) to an inhibitor of acid secretion in the range from 0.01 / 1 to 100/1. (10) A method for the veterinary treatment of an animal infected with Helicobacter pylori, comprising * administering an effective amount of the cephem (I) compound to an animal in need of such treatment. (11) The method of item (10) above, wherein the cephem compound (I) is administered to the animal in combination with an acid secretion inhibitor in a weight ratio of the cephem (I) compound to an inhibitor. of acid secretion in the range from 0.01 / 1 to 100/1. To illustrate the usefulness of the object compound (I), the data of the pharmacological tests of the compound representative of the compound (I) are shown in the following.

Test 1 (Antimicrobial activity against Helicobacter pylori Test Method Antimicrobial activity against Helicobacter pylori, determined by the agar plate double dilution method described below. Helicobacter pylori was grown on a Brucella agar plate containing 3% horse serum and 2% starch at 37 ° C for 3 days under 10% C02, and suspended in a Brucella broth at a McFarland turbidity. No. 1. This suspension was inoculated onto Brucella agar supplemented with 7% horse blood containing increasing concentrations of the test compound, and the minimum inhibitory concentration (MIC) was expressed in terms of μg / ml after incubation at 37 ° C for 3 days under 10% C02.

Test Compounds Salt of 7β- (2-phenylacetamido) -3- (5-aminomethyl-1,3,4-thiadiazol-2-yl) -thio-3-cephem-4-carboxylic acid trifluoroacetic acid Test results MIC (μg / ml) Test strain Test compound H. pylori FP 1757 < 0.02 Test 2 (Therapeutic effects in the mouse model) Test Method 1.5 ml of approximately 10 8 cfu / ml of H. pylori FP 1757 was inoculated orally into 4-week-old male ICR mice (Nippon SLC, Hamamatsu, Japan) that had been fasted overnight. Four days after infection, the test compound was orally administered to the mice, in the dose of 0.32 mg / g / time two times per day, for 4 days. The test compound was suspended in 0.5% methylcellulose and administered to the mice. The mice were sacrificed at 2 weeks after the final administration, and the gastric mucosa was scraped and homogenized in 1 ml of 0.1 M phosphate buffered saline. 0.1 ml aliquots were inoculated onto Brucella agar plates containing 3% of horse serum, 2% starch and antibiotics. All plates were incubated at 37 ° C under 10% C02 for 4 or 5 days. The colonies that grew on the plates were counted, and the therapeutic effect was evaluated.

Test Compound 7β- [2- (2-Thienyl) acetamido] -3- (4-carboxymethyl-1-thiazol-2-yl) thio-3-cephem-4-carboxylic acid (the compound of Example 72).

Result of the Test Test 3 (Subacute toxicity) Test Method The test compound suspended in 0.5% methylcellulose was orally administered to male rats in a dose of 100 or 32 mg / kg / day for 2 weeks.

Test Compound 7β- (2-phenylacetamido) -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cephem-4-carboxylic acid (the compound of Example 14).

Result of the Test The following Preparations and Examples are given for the purpose of illustrating the present invention in more detail.

Preparation 1 To a solution of 2-mercapto-4-thiazole-ethyl acetate (203 mg) in 1,4-dioxane (1.0 ml) was added ßl 1 N sodium hydroxide solution (2.0 ml) at room temperature. After stirring at the same temperature for 2 hours, the solution was poured into a mixture of ethyl acetate and water, and adjusted to pH 8.0 with 1N hydrochloric acid. The separated aqueous solution was adjusted to pH 3.0 with hydrochloric acid 1 N, and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazoleacetic acid. (120 mg). NMR (DMSO-d6, d): 3.31 (1 H, sa), 3.54 (2 H, s), 6.72 (1 H, s), 12.8 (1 H, sa) Preparation 2 To a mixture of 2-mercapto-4-thiazole-ethyl acetate (203 mg) in an ammonia solution (25%) (1.0 ml) was added ammonium chloride (5.3 mg) at room temperature. After stirring at the same temperature for 8 hours, the solution was poured into a mixture of tetrahydrofuran and saturated sodium chloride solution, and adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with tetrahydrofuran twice. The combined organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give 2-mercapto-4-thiazolacetamide (171 mg). NMR (DMSO-d6, 5): 3.36 (2 H, s), 6.65 (1 H, s), 7.-08 (1 H, sa), 7.47 (1 H, sa), 13.07 (1 H, sa APCI-MASS (m / z): 175 (M + H) + Preparation 3 To a mixture of sodium hydride (24 mg) and N, N-dimethylformamide (4.0 ml) was added a solution of dimethylamine (54 mg) in tetrahydrofuran (320 μl) at -10 ° C. After stirring at room temperature for 1 hour, 2-mercapto-4-thiazole-ethyl acetate (203 mg) was added to the mixture at room temperature. After stirring at room temperature for 3 hours, the mixture was poured into a mixture of water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate) to give N, N-dimethyl-2-mercapto-4-thiazolacetamide (72 mg). NMR (DMSO-d6, d): 2.84 (3 H, s), 3.00 (3 H, s), 3.62 (2 H, s), 6.63 i H, s), 13.0 (1 H, s) APCI-MASS (m / z): 203 (M + H) 'Preparation 4 To a solution of 2-mercapto-4-methyl-5-thiazole-ethyl acetate (217 mg) in tetrahydrofuran (5.0 ml) was added hydride of lithium and aluminum (38 mg) with ice cooling. After stirring at 60 ° C for 2 hours, the mixture was poured into a mixture of tetrahydrofuran and water, and adjusted to pH 3.0 with 1N hydrochloric acid. The separated organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: hexane / ethyl acetate = 2/3) to give 5- (2-hydroxyethyl) -2-mercapto-4-methylthiazole (89 mg). NMR (DMSO-ds, d): 2.05 (3 H, s), 2.59 (2 H, t, J = 6.1 Hz), 3.48 (2 H, dt, J = 6.1 and 5.2 Hz), 4.84 (1 H, t, J = 5.2 Hz), 12.9 (1 H, sa) APCI-MASS (m / z): 176 (M + H) + Preparation 5 4- (2-Hydroxyethyl) -2-mercaptot-iazole was obtained according to a manner similar to that of Preparation 4.

NMR (DMSO-d6, d): 2.59 (2 H, t, J = 5.9 Hz), 3.61 (2 H, dt, J = 6.3 and 5.2 Hz), 4.77 (1 H, t, J = 5.2 Hz), 6.59 (1 H, s), 13.1 (1 H, sa) APCI-MASS (m / z): 162 (M + H) tc; The following compounds (Preparations ß and 7_) were obtained according to a manner similar to that of Preparation 1. 0 Preparation β 4- (2-Carboxyethyl) -2-mercaptothiazole NMR (DMSO-ds, d): 2.5-2.8 (4 H, m), 6.58 (1 H, s), 12. 27 (1 H, sa), 13.13 (1 H, sa) # 5 Preparation 7 4- (Carboxymethyl) -2-mercapto-4,5,6,7-tetrahydrobenzothiazole NMR (DMSO-ds, d): 1.4-2.1 (4 H, m), 2.3-2.6 (3 H , m), 2. 7-2.9 (1 H, m), 2.8-3.1 (1 H, m), 12.87 (1 H, sa) 0 APCI-MASS (m / z): 230 (M + H) + Preparation 8 The following compound was obtained according to a manner similar to that of Preparation 2. 4- (2-Carbamoylethyl) -2-mercaptothiazole NMR (DMSO-d ^, d): 2.3-2.6 (2 H, m ), 2.66 (2 H, t, J = 7.2 Hz), 6.51 (1 H, s), 6.87 (1 H, sa), 7.36 (1 H, sa), 13.11 (1 H, sa) Preparation 9 To a solution of ammonium dithiocarbamate (NH2C (S) S -NH4) (1.10 g) in water (10 ml) were added ethyl bromopyruvate (1.95 g) and ethanol (5 ml) with ice cooling. After stirring at room temperature for 1 hour, the mixture was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution (x2), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give 4-e-toxicarbonyl-2-mercaptothiazole (1.21 g). NMR (DMS0-d, d): 1.25 (3 H, t, J = 7.1 Hz), 4.20 (2 H, c, J = 7.1 Hz), 10.97 (1 H, s) APCI-MASS (m / z) : 190 (M + H) + Preparation 10 The following compound was obtained according to a manner similar to that of Preparation 9. 4 - . 4-Ethoxycarbonylmethyl-2-mercapto-4, 5, β, 7-tetrahydro-benzothiazole NMR (DMSO-de, d): 1.1-1.3 (3 H, m), 1.4-2.0 (4 H, m), 2.3- 2.6 (3 H, m), 2.7-2.9 (1 H, m) 2.9-3.1 (1 H, m), 4.0-4.2 (2 H, m), 12.9 (1 H, m) APCI-MASS (m / z): 258 (M + H) t Preparation 11 To a mixture of 4-ethoxycarbonyl-2-mercapto-thiazole (150 mg) in ammonia solution (25%) (0.8 ml) was added ammonium chloride (4.2 mg) at room temperature. After stirring at the same temperature for 8 hours, the solution was poured into a mixture of tetrahydrofuran and saturated sodium chloride solution, and adjusted to pH 3.0 with 1 N hydrochloric acid. The separated tetrahydrofuran solution was washed with saturated solution of sodium chloride, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: chloroform / methanol) to give 4-carbamoyl-2-mercaptothiazole (70 mg). NMR (DMSO-d6, d): 7.40 (1 H, s), 7.45 (1 H, sa), 7.62 (1 H, sa) APCI-MASS (m / z): 161 (M + H) + "* Preparation 12 To a solution of levulinic acid (19.0 g) in methanol (328 ml) was added bromine (26.2 g) at room temperature After stirring at room temperature for 4 hours and at reflux for 1 hour, the methanol was evaporated The organic layer was washed with water, aqueous sodium hydrogen carbonate and saturated sodium chloride solution, and dried over magnesium sulfate and evaporated under pressure. The residue was distilled (70-75 ° C / l .36 x 10"3 kg / cm2, [1 mmHg]) to give the methyl 5-bromolevulinate (15.0 g). NMR (CDC13, d): 2.66 (2 H, t, J = 6.1 Hz), 2.96 (2 H, t, J = 6.1 Hz), 3.69 (3 H, s), 3.96 (2 H, s) Preparation 13 To a mixture of methyl 5-bromolevulinate (1.22 g), water (5.2 ml) and ethanol (2.6 ml) was added ammonium dithiocarbamate (642 mg) at room temperature. After stirring at room temperature for 2 hours, the resulting crystals were collected by filtration, and washed with a cold mixture of water and ethanol at the beginning, and diisopropyl ether (x 2) to give 4- (2-methoxycarbonylethyl) -2-mercaptothiazole (0.61 g).

NMR (DMSO-dβ, d): 2.6-2.8 (4 H, m), 3.60 (3 H, s), 6.59 (1 H, s), 13.15 (1 H, sa) APCI-MASS (m / z) : 204 (M + H) * Preparation 14 To a solution of 2-formamido-4-carboxymethyl thiazole (2.0 g) in tetrahydrofuran (20 ml) was added N-chlorosuccinimide (1.58 g), and stirred at room temperature overnight. N-chlorosuccinimide (0.5 g) was added to the reaction mixture and the same temperature was stirred overnight. The reaction mixture was evaporated under reduced pressure, and purified by column chromatography on silica gel (SiO2 = 200 ml, chloroform, methanol: acetic acid = 20: 1: 0.1) to give two fractions. Fraction 1 (the upper spot by TLC) was purified by column chromatography on silica gel (SiO2 = 200 ml, methanol: chloroform = 2: 8), then the elution was evaporated under reduced pressure. The residue was dissolved in a mixture of water and ethyl acetate, adjusted to pH 8.7 with saturated sodium hydrogen carbonate, and washed with ethyl acetate (x2). The aqueous layer was adjusted to pH 3.0 with 1N hydrochloric acid, extracted with ethyl acetate (x2), dried over magnesium sulfate, and evaporated under reduced pressure to give ^ a white solid, which was precipitated from ethyl acetate and n-hexane to give 5-chloro-2-formamido-4-carboxymethylthiazole (694 mg, 29.3%) as a white powder. On the other hand, reaction 2 (the lower spot by TLC) was evaporated under reduced pressure, and precipitated from chloroform and methanol and isopropyl ether to give the acid 5-chloro-2-formamidothiazol-4-yl- (R, S ) -chloromethylcarboxylic acid (870 mg, 39.4%). (Upper spot) NMR (DMSO-d6, d): 3.60 (2 H, s), 8.51 (1 H, s), 12.54 (1 H, sa) APCI-MASS (m / z): 221 (M + H ) + (Lower spot) NMR (DMSO-d6, 8): 5.28 (1 H, s), 8.50 (1 H, s) APCI-MASS (m / z): 255 (M + H) + Preparation 15 To a mixture of 5-amino-2-mercaptot-iazole (ß.ßl g) in water (34 ml) and acetic acid (17 ml) was added a solution of sodium cyanate (6.50 g) in water (55 ml) at 35 ° C. After stirring at the same temperature 2 hours, the solution was poured into a mixture of water, tetrahydrofuran and ethyl acetate, and adjusted to pH 3.0 with 1 N hydrochloric acid. The separated organic layer was washed with saturated sodium chloride solution (x 2), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give 5-ureido-2-mercaptothiazole (577 mg). NMR (DMSO-d, d): 4.25 (2 H, s), 7.45 (1 H, s), 10.63 (1 H, sa), 13.36 (1 H, sa) Preparation 16 To a mixture of 2-mercaptothiazol-4-yl-acetamide (174 mg) and tetrahydrofuran (10 ml) was added Lawesson's reagent (202 mg) at room temperature. After stirring at room temperature overnight, the solution was poured into a mixture of water and ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate) to yield 2-mercapto-thiazol-4-yl-ioaceta ida (188 mg). NMR (D SO-dí d): 3.73 (2 H, s), 6.68 (1 H, s), 9.33 (1 H, sa), 9.69 (1 H, sa), 13.11 (1 H, sa) APCI- MASS (m / z): 191 (M + H) + Preparation 17 To a solution of 2-cyclohexanone-ethyl acetate (1.0 g) in dimethoxyethane (15 ml) was added bromine (911 mg) with ice-cooling. After stirring at room temperature for 1 hour, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with aqueous sodium hydrogen sulfide, sodium hydrogen carbonate and saturated sodium chloride in that order, and dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give 2-bromo-6-cyclohexanone-ethyl acetate (258 mg). NMR (CDCls, d): 1.2-1.3 (3 H, m), 1.3-1-9 (2 H, m), 2.0-2.4 (5H, m), 2.6-2.9 (1 H, m), 3.6- 3.9 (1 H, m), 4.1-4.3 (2 H, m), 4.3-4.5 (1 H, m) APCI-MASS (m / z): 263 (M + H) + Preparation 18 To a solution of benzhydryl 7β- (2-phenylacetamido) -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylate (9.0 g) in a mixture of dichloromethane (27 ml) and anisole (9 ml) was added trifluoroacetic acid (18 ml) under ice cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into diisopropyl ether (380 ml). The precipitate was collected by filtration, and dried to give 7β- (2-phenylacetamido) -3-trifluoro-methanesulfonyloxy-3-cephem-4-carboxylic acid (7.55 g) • NMR (DMSO-ds, d): 3.48 and 3.58 (2 H, ABq, J = 14 Hz), 3.83 and 4.00 (2 H, ABq, J = 18 Hz), 5.26 (1 H, d, J = 5 Hz), 5.81 (1 H, dd, J = 5 and 8 Hz), 7.1-7.4 (5 H, m), 9.24 (1 H, d, J = 8 Hz) Preparation 19 To a mixture of ethyl 4- (bromoacetyl) benzoate (2 g), water ((15 ml) and ethanol (14 ml) was added ammonium dithiocarbamate (813 mg) with stirring at room temperature. for 1 hour at the same temperature, and the resulting crystals were collected by filtration.The crystals were added to a mixture of water (15 ml) and ethanol (15 ml), and the mixture was heated to reflux for 1.5 hours under stirring. Stirring was continued for 30 minutes at 10 ° C to give crystals, which were collected by filtration and dried to give ethyl 4- (2-mercaptothiazol-4-yl) benzoate (1.15 g). IR (KBr): 1699, 1608, 1587, 1456, 1290 cm "1 NMR (DMSO-d6, 8): 1.34 (3 H, t, J = 7.1 Hz), 4.33 (2 H, c, J = 7.1 Hz ), 7.53 (1 H, s), 7.96 (4 H, dd, J = 8.6 and 20.6H z), 13.8 (1 H, s) APCI-MASS (m / z): 266 (M + H) + Preparation 20 The following compound was obtained according to a manner similar to that of Preparation 1. 4- (2-mercaptotriazol-4-yl) benzoic acid IR (KBr): 1685, 1608, 1556, 1477, 1403, 1249 cm "1 NMR (DMS0-d6, d): 7.51 (1 H, s), 7.94 (4 H, dd, J = 8.6 and 22.1 Hz), 13.77 (1 H, s) APCI-MASS (m / z): 238 (M + H) t Example 1 To a solution of 2-mercapto-4-thiazoleacetic acid (105 mg) in tetrahydrofuran (1.1 ml) and dimethoxyethane (1.1 ml) was added potassium t-butoxide (119 mg) at -10 ° C, and the solution it was stirred at the same temperature for 20 minutes. On the other hand, a solution of benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylate (267 mg) in tetrahydrofuran (1.3 ml) and dimethoxyethane (1.3 ml) was added to the solution of up to -15 ° C. After stirring under ice cooling for 2 hours, the solution was poured into a mixture of water, ethyl acetate and tetrahydrofuran, and adjusted to pH 3.0 with 1N hydrochloric acid. The separated organic layer it was washed with a saturated solution of sodium color, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / methanol = 8/1) to give 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3 benzhydryl-cephem-4-carboxylate as the potassium salt (108 mg). NMR (DMSO-d6, d): 3.4-3.8 (6 H, m), 5.16 (1 H, d, J = 3.9 Hz), 5.52 (1 H, dd, J = 3.9 and 7.7 Hz), 6.87 (1 H, s), 7.2-7.5 (15 H, m), 7.61 (1 H, s), 9.32 (1 H, d, J = 7.7 Hz) FAB-MASS (m / z): 696 (M + H) + The following compounds (Example 2 to 9) were obtained according to a manner similar to that of Example 1.

Example 2 Benzyltryl-7-benzyl-2-phenylacetamido-3 - (4-carbamoylmeththiazol-2-yl) thio-3-cephem-4-carboxylate NMR (DMSO-ds, d): 3.53 (2 H, dd, J = 13.9 and 17.3 Hz), 3.57 (2 H, s), 3.54 and 3.76 (2 H, ABq, J = 17.7 Hz), 5.25 (1 H, d, J = 5.0 Hz), 5.82 (1 H, dd , J = 5.0 and 8.4 Hz), 6.97 (1 H, s), 7.01 (1 H, sa) "7.2-7.5 (16 H, m), 7.56 (1 H, s), 9.26 (1 H, d, J = 8.4 Hz) APCI-MASS (m / z): 657 (M + H) + EXAMPLE 3 Potassium salt of benzhydryl 7β- (2-phenylacetamido) -3- (5-carbo-imethyl-4-methylthiazol-2-yl) thio-3-cephem-4-benzhydrylcarboxylate NMR (DMS0-d6, d) : 2.27 (3 H, s), 3.4-3.9 (6 H, m), 5.26 (1 H, d, J = 5.0 Hz), 5.82 (1 H, dd, J = 5.0 and 8.4 Hz), 6.96 (1 H, s), 7.1-7.5 (15 H, m), 9.26 (1 H, d, J = 8.4 Hz) Example 4 Benzyltryl-3 - (4-N, N-dimet-il-carbamoylmethyl-thiazol-2-yl) thio-3-cephem-4-carboxylate benzhydryl NMR (DMSO-d6, d) : 2.83 (3 H, s), 3.03 (3 H, s), 3.53 (2 H, d, J = 3.8 Hz), 3.54 and 3.75 (2 H, ABq, J = 17.4 Hz), 3.84 (2 H, s), 5.25 (1 H, d, J = 5.0 Hz), 5.81 (1 H, dd, J = 5.0 and 8.4 Hz), 6.97 (1 H, s), 7.1-7.5 (15 H, m), 7.55 (1 H, s), 9.26 (1 H, d, J = 8.4 Hz) Example 5 7β- (2-phenylacetamido) -3- (5-hydroxymethyl-1,3,4-thiadi-azole-2-yl) benzhydryl thio-3-cephem-4-carboxylate NMR (DMSO-ds, d): 3.52 (2 H, d, J = 4.1 Hz), 3.61 and 3.89 (2 H, ABq, J = 17.8 Hz), 4.84 (2 H, s), 5.28 (1 H, d, J = 5.0 Hz), 5.87 (1 H, dd, J = 5.0 and 8.4 Hz), 6.30 (1 H, sa), 6.98 (1 H, s) , 7.2-7.5 (15 H, m), 9.30 (1 H, d, J = 8.4 Hz) Example 6 7β- [2- (3-thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (CDC13, d ): 3.44 and 3.70 (2 H, ABq, J = 17.9 Hz), 3.66 (2 H, s), 4.98 (2 H, s), 5.00 (1 H, d, J = 5.0 Hz), 5.88 (1 H , dd, J = 5.0 and 9.1 Hz), 6.76 (1 H, d, J = 9.1 Hz), 6.96 (1 H, s), 6.9-7.4 (14 H, m) Example 7 7β- [2- (2-thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (CDCl 3, d ): 3.43 and 3.68 (2 H, ABq, J = 18.1 Hz), 3.85 (2 H, s), 5.00 (2 H, s), 5.01 (1 H, d, J = 5.1 Hz), 5.89 (1 H , dd, J = 5.1 and 9.1 Hz), 6.86 (1 H, d, J = 9.1 Hz), 6.9-7.0 (3 H, m), 7.1-7.4 (12 H, m) Example 8 7ß- (2- phenylacetamido) -3- [4- (2-hydroxyethyl) -thiazol-2-yl] t-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-ds, d): 2.86 (2 H, t, J = 6.7 Hz), 3.4-3.9 (6 H, m), 4.69 (1 H, t, J = 5.3 Hz), 5.26 (1 H, d, J = 5.0 Hz), 5.82 (1 H, dd, J = 5.0 and 8.4 Hz), ß.97 (1 H, s), 7.2-7.5 (16 H, m), 9.27 (1 H, d, J = 8.4 Hz) EXAMPLE 9 Benzyl-3-methyl-3-methyl-thiazol-2-yl] thio-3-cephem-4-carboxylic acid benzylhydryl-3 - [5- (2-hydroxyethyl) -4-methyl-thiazol-2-yl] thio-3-cephem-4-carboxylate NMR (DMSO-de, d): 2.29 (3 H, s), 2.86 (2 H, t, J = 6.1 Hz), 3.4-3.8 (6 H, m), 4.92 (1 H, t, J = 5.2 Hz), 5.25 (1 H, d, J = 4.9 Hz), 5.80 (1 H, d, J = 4.9 and 8.3 Hz), 6.95 (1 H, s), 7.2-7.6 (15 H, m), 9.25 (1 H, d, J = 8.4 Hz).

Example 10 To a solution of 2-mercapto-4-methyl-5-thiazolacetamido (489 mg) in tetrahydrofuran (4.9 ml) and dimethoxyethane (4.9 ml) was added potassium t-butoxide (224 mg) at -10 ° C, and the solution was stirred at room temperature for 20 minutes. On the other hand, a solution of benzhydryl (1.16 g) 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylate in tetrahydrofuran (5.8 ml) and dimethoxyethane (5.8 ml) was added to the solution of at -15 ° C. After stirring under ice cooling for 2 hours, the solution was poured into a mixture of water and ethyl acetate. The resulting crystals were collected by filtration, washed with water and ethyl acetate to give 7β- (2-phenylacetamido) -3- (5-carbamoylmethyl-4-methylthiazol-2-yl) thio-3-cephem-4-carboxylate of benzhydryl (355 mg). The ethyl acetate layer of the filtrate was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue, and the resulting crystals were collected by filtration, and washed with ethyl acetate to give a second crop of crystals of the object compound (494 mg). NMR (DMSO-d6, d): 2.28 (3 H, s), 3.52 (2 H, d, J = 3.2 Hz), 3.53 and 3.75 (2 H, ABq, J = 17.7 Hz), 3.62 (2 H, s), 5.26 (1 H, d, J = 4.9 Hz), 5.81 (1 H, dd, J = 4.9 and 8.4 Hz), 6.96 (1 H, s), 7.17 (1 H, sa), 7.2-7.5 (15 H, m), 7.64 (1 H, sa), 9.28 (1 H, d, J = 8.4 Hz).

Example 11 To a solution of 5-N, N-dimethylaminomethyl-2-mercapto-1,3,4-thiadiazole (364 mg) in a mixture of tetrahydrofuran (7 ml) and 1,2-dimethoxyethane (7 ml) was added potassium t-butoxide (194 mg) at ice-cooling temperature with stirring, and the mixture was stirred at the same temperature for 30 minutes. 7-Benzyl-4-carboxylic acid benzhydryl (1.0 g) was added to the solution obtained at the same temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into a mixture of 1N hydrochloric acid (1.64 ml), water (30 ml) and ethyl acetate (30 ml), the organic layer was washed with water and saturated aqueous sodium chloride, dried over Magnesium sulfate and concentrated in vacuo The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / n-hexane = 3/1) to give 7β- (2-phenylacetamido-3- (5- N, -dimethylaminomethyl-1,3,4-thiadi-azol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl ester (310 mg). NMR (DMSO-d6, d): 2.23 (6H, s), 3.53 (2 H, m), 3.63 and 3.93 (2 H, ABq, J = 18 Hz), 3.83 (2 H, m), 5.28 (1 H, d, J = 5 Hz), 5.88 (1 H, dd, J = 5 and 8 Hz), 6.99 (1 H, s), 7.2-7.4 (15 H, m), 9.30 (1 H, d, J = 8 Hz).

Example 12 To a solution of 5- tert-butoxycarbonylamino-methyl-2-mercapto-1,3,4-thiadiazole (580 mg) in a mixture of tetrahydrofuran (3 ml) and 1,2-dimethoxyethane (3 ml) was added potassium tert-butoxide (239 mg) at -9 ° C with stirring, and the mixture was stirred at -9 ° -5 ° C for 30 minutes. A solution of benzhydryl 7β- (2-phenylacetamido) -3- "5-methanesulfonyloxy-3-cephem-4-carboxylate (1.23 g) in a mixture of tetrahydrofuran (6 ml) and 1,2-dimethoxyethane (6 ml) was added. The solution was added at -8 ° C, and the mixture was stirred at -5 ° -0 ° C for 3.5 hours.The reaction mixture was poured into an ice-water mixture (50 ml) and ethyl acetate. (50 ml) The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo.The residue was triturated with diethyl ether to give 7β- (2-phenylacetamido) -3- ( 5-tert-5-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl) thio-3- * cephem-4-carboxylic acid benzhydryl ester (0.82 g) NMR (DMSO-de, d): 3.5 (2 H, ), 3.57 and 3.89 (2 H, ABq, J = 18 Hz), 4.47 (2 H, d, J = 5 Hz), 5.27 (1 H, d, J = 5 Hz), 5.86 (1 H, dd, J = 5 and 8 Hz), 6.99 (1 H, s), 7.2-0 7.4 (15 H,), 7.83 (1 H, m), 9.28 (1 H, d, J = 8 Hz) FAB-MASS (m / z): 730.2 (M +).

Example 13 To a mixture of potassium salt of 7β- (2-5-phenylacetamido) -3- (4-carboxymethyl-iazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl ester (1.10 g), anisole (1.10 g) ml) and dichloromethane (3.30 ml) was added trifluoroacetic acid (2.20 ml) at 15 ° C. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran and water, and adjusted to pH 7.2 with aqueous sodium bicarbonate. The separated aqueous solution was adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue, and the resulting crystals were collected by filtration, to give 7β- (2-phenylacetamido) -3- (-carboxymethyl thiazol-2-yl) thio-3-cephem-4-carboxylic acid. lyico (595 mg). IR (KBr): 1775, 1710, 1654, 1537 cm "1 NMR (DMSO-d6, d): 3.48 and 3.73 (2 H, ABq, J = 17.5 Hz), 3.52 (2 H, dd, J = 14 y 17.6 Hz), 3.74 (2 H, s), 5.19 (1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 5.0 and 8.3 Hz), 7.1-7.4 (5 H, m), 7.59 (1 H, s), 9.19 (1 H, d, J = 8.3 Hz), FAB-MASS (m / z): 492 (M + H) +.

The following compounds (Example 14 to 2JL_) were obtained according to a manner similar to that of Example 13.

EXAMPLE 14 7β- (2-Phenylacetamido) -3- (4-carbamoyl-methyl thiazol-2-11) thio-3-cephem-4-carboxylic acid IR (KBr): 3440, 3284, 1776, 1664, 1539, 1357 cm "1 NMR (DMSO-de, d): 3.52 (2 H, dd, J = 13.9 and 17.8 Hz), 3.55 (2 H, s), 3.50 and 3.74 (2 H, ABq, J = 17.6 Hz), . 20 (1 H, d, J = 4.9 Hz), 5.74 (1 H, dd, J = 4.9 and 8.4 Hz), 6.99 (1 H, sa), 7.1-7.4 (5 H *, m), 7.43 (1 H, sa), 7. 53 (1 H, s), 9.21 (1 H, d, J = 8.4 Hz). FAB-MASS (m / z): 491 (M + H) +.

Example 15 7β- (2-Phenylacetamido) -3- (5-carboxymethylmethyl-thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1776, 1718, 1657, 1539, 1367 cm " 1 NMR (DMSO-de, d): 2.26 (3 H, s), 3.52 (2 H, dd, J = 13.8 and 17.7 Hz), 3.48 and 3.72 (2 H, ABq, J = 17.6 Hz), 3.83 ( 2 H, s), 5.20 (1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 4. 9 and 8.4 Hz), 7.1-7.4 (5 H, m), 9.22 (1 H, d, J = 8.4 Hz). FAB-MASS (m / z): 506 (M + H) +.

Example 16 7β- (2-Phenylacetamido) -3- (4-N, N-dimethylcarbamoyl-methylthiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 3286, 1776, 1655, 1541, 1365 cm-1 NMR (DMSO-de, d): 2.84 (3 H, s), 3.04 (3 H, s), 3.52 (2 H, s), 3.48 and 3.73 (2 H, ABq, J = 17.6 Hz ), 3.83 (2 H, s), 5.19 (1 H, d, J = 4.9 Hz), 5.74 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H,), 7.52 (1 H, s), 9.21 (1 H, d, J = 8.3 Hz). FAB-MASS (m / z): 519 (M + H) +.

Example 17 7β- (2-Phenylacetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-ce fem-4-carboxylic acid IR (KBr): 1784, 1662, 1533 cm "1 NMR (DMSO-de, d): 3.52 (2 H, d, J = 4.2 Hz), 3.55 and 3.87 (2 H, ABq, J = 17.7 Hz), 4.83 (2 H, s), 5.23 (1 H, d, J = 5.0 Hz), 5.79 (1 H, dd, J = 5.0 and 8.4 Hz), 6.29 (1 H, sa), 7.2-7.4 (5 H, m), 9.24 (1 H, d, J = 8.4 Hz) FAB-MASS (m / z): 465.0 (M + H) +.

Example 18 7β- [2- (3-Thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1776, 1689, 1652, 1537 cm "1 NMR (DMSO-d6, d): 3.54 (2 H, s), 3.56 and 3.88 (2 H, ABq, J = 17.6 Hz), 4.83 (2 H, s), 5.24 (1 H, d, J = 5.0 Hz), 5.80 (1 H, dd, J = 5.0 and 8.4 Hz), 6.30 (1 H, sa), - 7.0-7.5 (3 H, m), 9.21 (1 H, d, J = 8.4 Hz.) FAB-MASS (m / z): 470.9 (M + H) +.

Example 19 7β- [2- (2-Thienyl) acetamido] -3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1776, 1689, 1652, 1539 c "1 NMR (DMSO-de, d): 3.56 and 3.88 (2 H, ABq, J = 17.7 Hz), 3.76 (2 H, s), 4.83 (2 H, s), 5.25 (1 H, d, J = 5.0 Hz), 5.80 1 H, dd, J = 5.0 and 8.4 Hz), 6.30 (1 H, sa), 6.9-7.0 (2 H, m), 7.36 (1 H, dd, J = 1.6 and 4.9 Hz), 9.28 (1 H, d, J = 8.4 Hz), FAB-MASS (m / z): 470.9 (M + H) +.

Example 20 7β- (2-phenylacetamido) -3- (2-hydroxyethyl) thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1776, 1699, 1656, 1539 c "1 NMR (DMSO-de, d): 2.84 (2 H, t, J = 6.7 Hz), 3.3-3.8 (6 H, m), 4.67 (1 H, sa), 5.21 (1 H, d, J = 4.9 Hz), 5.75 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H, m), 7.45 (1 H, s), 9.22 (1 H, d, J = 8.3 Hz).

FAB-MASS (m / z): 477.9 (M + H) +.

Example 21 7β- (2-Phenylacetamido) -3- [5- (2-hydroxyethyl) -4-methylthiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1778, 1655, 1541 c "1 NMR (DMSO-de, d): 2.28 (3 H, s), 2.86 (2 H, t, J = 6.1 Hz), 3.4-3.8 (6 H, m), 4.91 (1 H, sa ), 5.19 (1 H, d, J = 4.9 Hz), 5.72 (1 H, dd, J = 4.9 and 8.4 Hz), 7.1-7.4 (5 H, m), 9.21 (1 H, d, J = 8.4 Hz). FAB-MASS (m / z): 492.1 (M + H) +.

Example 22 To a mixture of benzhydryl 7β- (2-phenylacetamido) -3- (5-carbamoylmethyl-4-methylthiazol-2-yl) thio-3-cephem-4-carboxylate (0.80 g), anisole (0.80 ml) and dichloromethane (2.40 ml) was added trifluoroacetic acid (1.60 ml) at 15 ° C. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran and water, and adjusted to pH 7.5 with aqueous sodium bicarbonate. The separated aqueous solution was washed with ethyl acetate, and adjusted to pH 3.0 with 1 N hydrochloric acid. The resulting crystals were collected by filtration, and washed with water to give 7β- (2-phenylacetamido) -3- acid ( 5-carbamoylmethyl-4-methylthiazol-2-yl) thio-3-cephem-4-carboxylic acid (445 mg). IR (KBr): 3423, 3298, 1778, 1660, 1540, 1365 cm "1 NMR (DMSO-de, d): 2.28 (3 H, s), 3.52 (2 H, dd, J = 13.6 and 17.5 Hz) , 3.48 and 3.71 (2 H, ABq, J = 17.5 Hz), 3.61 (2 H, s), 5.20 (1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 4.9 and 8.4 Hz ), 7.14 (1 H, sa), 7.1-7.4 (5 H,), 7.62 (1 H, sa), 9.24 (1 H, d, J = 8.4 Hz) FAB-MASS (m / z): 505 (M + H) +.

EXAMPLE 23 To a solution of benzhydryl 7β- (2-phenylacetamido) -3- (5-N, N-dimethylaminomethyl-1,3,4-thiadiazol-2-yl) thio-3-cephene-4-carboxylate) mg) in a mixture of dichloromethane (0.9 ml) and anisole (0.47 ml) was added trifluoroacetic acid (0.6 ml) under ice cooling. The mixture was stirred at room temperature for one hour. The reaction mixture was poured into diisopropyl ether (30 ml) and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (10 ml), tetrahydrofuran (10 ml) and ethyl acetate (20 ml). The mixture was adjusted to pH 2.0 with 1N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate, to give 7β- (2-phenylacetamido] -3- (5-N, N-dimethylaminomethyl-1, 3,4-thiadiazol-2-yl) thio-3-cephem-4 acid. carboxylic (150 mg) IR (Nujol): 3300-3200, 1770, 1720, 1660, 1530 cm "1 NMR (DMSO-de, d): 2.79 (6 H, s), 3.4-3.6 (2 H, m), 3.61 and 3.91 (2 H, ABq, J = 18 Hz), 4.78 (2 H, sa), 5.24 (1 H, d, J = 5 Hz), 5.79 (1 H, dd, J = 5 y 8 Hz), 7.2-7.3 (5 H, m), 9.26 (1 H, d, J = 8 Hz), FAB-MASS (m / z): 492 (M + H) +.

Example 24 To a solution of benzhydryl 7β- (2-phenylacetamido] -3- (5-tert-butoxycarbonylaminomethyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylate (683 mg) In a mixture of dichloromethane (2.1 ml) and anisole (0.7 ml), trifluoroacetic acid (1.4 ml) was added under ice cooling.The mixture was stirred at the same temperature for 30 minutes, and at room temperature for 3 hours. The reaction was poured into diisopropyl ether (70 ml), the precipitate was collected by filtration, and dried to give the trifluoroacetic acid salt of 7β- (2-phenylacetamido) -3- (5-aminomethyl- 1, 3, 4 -thiadiazol-2-yl) thio-3-cephem-4-carboyl (525 mg). IR (Nujol): 1770, 1660, 1530, 1200 cm "1 NMR (DMSO-de, d): 3.4-3.6 ( 2 H, m), 3.49 and 3.87 (2 H, ABq, J = 17 Hz), 4.56 (2 H, s), 5.21 (1 H, d, J = 5 Hz), 5.76 (1 H, dd, J = 5 and 8 Hz), 7.27 (5 H, m), 9.22 (1 H, d, J = 8 Hz) FAB-MASS (m / z): 464.0 (M + H) +.

The following compounds (Examples 25 to 21_) were obtained according to a manner similar to that of Example 13.

Example 25 7β- (2-phenylacetamido) -3- [4- (2-methoxycarbonyl-ethyl) -thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1782, 1728, 1693, 1662, 1539 cm "1 NMR (DMSO-de, d): 2.70 (2 H, t, J = 7.1 Hz9, 2.97 (2 H, t, J = 7.4 Hz), 3.52 (2 H, d, J = 3.6 Hz), 3.59 (3 H, s), 3.47 and 3.73 (2 H, ABq, J = 17.5 Hz), 5.20 (1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 8.3 Hz ), 7.2-7.4 (5 H, m), 7.46 (1 H, s), 9.18 (1 H, d, J = 8.3 Hz), FAB-MASS (m / z): 520 (M + H) +.

Example 26 7β- (2-phenylacetamido) -3- [4- (2-carboxyethyl) thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1778, 1699, 1660, 1535 cm "1 NMR (DMSO-de, d): 2.61 (2 H, t, J = 7.3 Hz), 2.93 (2 H, t, J = 7.3 Hz), 3.52 (2 H, d, J = 4.3 Hz), 3.47 and 3.74 (2 H, ABq, J = 17.5 Hz), 5.20 (1 H, d, J = 4.9 Hz), . 74 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H, m), 7. 44 (1 H, s), 9.21 (1 H, d, J = 8.3 Hz). FAB-MASS (m / z): 506 (M + H) +.

Example 27 7ß- (2-phenylacetamido) -3- (5-ureidothiazol-2-yl) thio- 3-ce fem-4 -carboxylic acid (KBr) acid: 1772, 1664, 1527 cm "1 NMR (DMSO) -d6, d): 3.52 (2 H, d, J = 4.1 Hz), 3.53 and 3.81 (2 H, ABq, J = 17.5 Hz), 4.30 (2 H, s), 5.23 (1 H, d, J = 5.0 Hz), 5.75 (1 H, dd, J = 5.0 and 8.4 Hz), 7.1-7.4 (5 H, m), 7.99 (1 H, s), 9.21 (1 H, d, J = 8.4 Hz), 10.73 (1 H, s). FAB-MASS (m / z): 491 (M + H) +.

The following compounds (Elas 28 to 37) were obtained according to a manner similar to that of Example 22.

EXAMPLE 28 7β- (2-Phenylacetamido) -3- [4- (N-methyl-ylcarbamoyl-methyl) thiazol-2-yl) thio-3-cephem-4-carboxylic acid (KBr): 1776, 1658, 1652 , 1538 cm "1 NMR (DMSO-d6, d): 2.59 (3 H, d, J = 4.6 Hz), 3.52 (2 H, d, J = 4.1 Hz), 3.56 (2 H, s), 3.49 and 3.74 (2 H, ABq, J = 17.5 Hz), 5.20 (1 H, d, J = 4.9 Hz), 5.74 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H, m) , 7.52 (1 H, s), 7.89 (1 H, m), 9.20 (1 H, d, J = 8.3 Hz), FAB-MASS (m / z): 505 (M + H) +.

Example 29 7- (2-phenylacetamido) -3- (4-morpholinocarbonylmethyl-thiazol-2-yl) thio-3-cephem-4-carboxylate benzhydryl IR (KBr): 1776, 1683, 1654, 1540 cm "1 NMR (DMSO-d6, d): 3.4-3.6 (10 H, m), 3.48 and 3.73 (2 H, ABq, J = 17.5 Hz), 3.86 (2 H, s), 5.19 (1 H, d, J = 4.9 Hz), 5.76 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H, m), 7.54 (1 H, s), 9.19 (1 H, d, J = 8.3 Hz). FAB-MASS (m / z): 561 (M + H) +.

EXAMPLE 30 7β- (2-Phenylacetamido) -3- [4- (N- (2-pyridylmethyl) -carbamoylmethyl) thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1774, 1660, 1618, 1539 c "1 NMR (DMSO-d6, d): 3.52 (2 H, d, J = 3.8 Hz), 3.50 and 3.74 (2 H, ABq, J = 17.5 Hz), 3.70 (2 H, s), 4.39 (2 H, d, J = 5.9 Hz), 5.17 (1 H, d, J = 4.9 Hz), 5.74 (1 H, - dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (7 H,), 7.58 (1 H, s), 7.74 (1 H, dt, J = 1.8 and 7.7 Hz), 8.50 (1 H, d, J = 4.0 Hz), 8.61 (1 H, t, J = 6.0 Hz), 9.20 (1 H, d, J = 8.3 Hz), FAB-MASS (m / z): 582 (M + H) +.

Example 31 7β- (2-phenylacetamido) -3- (4-carbamoyl-thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1780, 1662, 1581, 1537 cm "1 NMR ( DMSO-d6, d): 3.53 (2 H, d, J = 4.5 Hz), 3.60 and 3.93 (2 H, ABq, J = 17.6 Hz), 5.22 (1 H, d, "J = 5.0 Hz), 5.78 (1 H, dd, J = 5.0 and 8.3 Hz), 7.2-7.4 (5 H, m) , 7. 65 (1 H, sa), 7.81 (1 H, sa), 8.31 (1 H, s), 9.23 (1 H, d, J = 8.3 Hz). FAB-MASS (m / z): 477 (M + H) +.

EXAMPLE 32 7β- (2-Phenylacetamido) -3- [4- (2-carbamoylethyl) -thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1774, 1683, 1660, 1531 cm "1 NMR (DMSO-d6, d): 2.3-2.5 (2 H, m), 2.90 (2 H, t, J = 7.7 Hz), 3.52 (2 H, d, J = 4.2 Hz), 3.46 and 3.73 (2 H, ABq, J = 17.5 Hz), 5.20 (1 H, d, J = 4.9 Hz), 5.74 (1 H, dd, J = 4.9 and 8.3 Hz), 6.77 (1 H, sa), 7.1 -7.3 (6 H, m), 7.40 (1 H, s), 9.19 (1 H, d, J = 8.3 Hz), FAB-MASS (m / z): 505 (M + H) +.

EXAMPLE 33 7β- [2- (3-Thienyl) acetamido] -3- (4-carbamoylmethyl-thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (Nujol): 1760, 1660, 1530 cm "1 NMR (DMSO-de, d): 3.55 (2 H, s), 3.55 (2 H, s), 3.51 and 3.75 (2 H, ABq, J = 17.7 Hz), 5.20 (1 H, d, J = 4.9 Hz), 5.75 (1 H, dd, J = 4.9 and 8.3 Hz), 6.9-7.1 (2 H, m), 7.25 (1 H, m), 7.4-7.6 (3 H,), 9.18 (1 H, d, J = 8.3 Hz.) FAB-MASS (m / z): 497 (M + H) +.

EXAMPLE 34 7β- [2- (3-Thienyl) acetamido] -3- (4- (2-carboxyethyl) -thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (Nujol): 1770, 1690 , 1650, 1530 c "1 NMR (DMSO-de, d): 2.61 (2 H, t, J = 7.3 Hz), 2.93 (2 H, t, J = 7.3 Hz), 3.54 (2 H, s), 3.47 and 3.75 (2 H, ABq, J = 17.5 Hz), 5.21 (1 H, d, J = 4.9 Hz), 5.74 (1 H, dd, J = 4.9 and 8.3 Hz), 7.0-7.1 (1 H, m), 7.2-7.3 (1 H, m), 7.44 (1 H, s), 7.4-7.5 (1 H,), 9.16 (1 H, d, J = 8.3 Hz). FAB-MASS (m / z): 512 (M + H) +.

Example 35 7β- [2- (2-Thienyl) acetamido] -3- (4-carbamoylmethyl-thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1765, 1660, 1530 cm "1 NMR (DMSO-de, d): 3.55 (2 H, s), 3.76 (2 H, s), 3.48 and 3.75 (2 H, ABq, J = 17.5 Hz), 5.21 (1 H, d, J = 4.9 Hz), 5.75 (1 H, dd, J = 4.9 and 8.3 Hz), 6.9-7.0 (2 H, m), 6.99 (1 H, sa), 7.36 (1 H, dd, J = 1.5 and 4.8 Hz) , 7. 44 (1 H, sa), 7.52 (1 H, s), 9.24 (1 H, d), J = 8.3 Hz). FAB-MASS (m / z): 497 (M + H) +.

Example 36 7β- [2- (2-Thienyl) acetamido] -3- [4- (2-carboxyethyl) -thiazol-2-yl] thio-3-cephem-4-carboxylic acid IR (Nujol): 1765, 1680, 1650, 1520 cm "1 NMR (DMSO-de, d): 2.61 (2 H, t, J = 7.4 Hz), 2.93 (2 H, t, J = 7.4 Hz), 3.5-3.9 (4 H, m), 5.22 (1 H, d, J = 4.9 Hz), 5.75 (1 H, dd, J = 4.9 and 8.4 Hz), 6.8-7.0 (2 H, m), 7.3-7.5 (2 H, m) , 9.23 (1 H, d, J = 8.4 Hz), FAB-MASS (m / z): 512 (M + H) +.

Example 37 7β- [2- (3-Thienyl) acetamido] -3- (4-carboxymethyl-thiazol-2-yl) thio-3-cephem-4-carboxylic acid IR (KBr): 1774, 1704, 1652, 1533 cm "1 NMR (DMSO-de, d): 3.54 (2 H, s), 3.74 (2 H, s), 3.47 and 3. 75 (2 H, ABq, J = 17.7 Hz), 5.20 (1 H, d, J = 4.9 Hz), 5.75 (1 H, dd, J = 4.9 and 8.4 Hz), 7.0-7.1 (1 H, m), 7.2-7.3 (1 H, m), 7.4-7.5 (1 H, m), 7.59 ( 1 H, s), 9. 19 (1 H, d, J = 8.4 Hz). FAB-MASS (m / z): 498 (M + H) +.

Example 38 To a solution of 4-carbamoyl-2-mercaptothiazole (450 mg) in tetrahydrofuran (27 ml) and dimethoxyethane (27 ml) was added potassium t-butoxide (242 mg) at -10 ° C, and the solution was added. stirred at the same temperature for 20 minutes. On the other hand, a solution of 7β- (2-phenylacetamido) -3-methansul-fonyloxy-3-cephem-4-benzhydrylcarboxylate (1.25 g) in tetrahydrofuran (12.5 ml) and dimethoxyethane (12.5 ml) was added to the solution from above to -15 ° C. After stirring under ice cooling for 2 hours, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give -7β- (2-phenylacetamido) -3- (4-carbamoylthiazol-2-yl) thio-3- Benzhydryl cefem-4-carboxylate (0.86 g). NMR (DMSO-d6, d): 3.54 (2 H, d, J = 4.0 Hz), 3.66 and 3.94 (2 H, ABq, J = 17.6 Hz), 5.27 (1 H, d, J = 5.0 Hz), 5.86 (1 H, dd, J = 5.0 and 8.4 Hz), 6.98 (1 H, s), 7.1-7.5 (15 H, m), 7.64 (1 H, sa), 7.78 (1 H, sa), 8.32 (1 H, s), 9.26 (1 H, d, J = 8.4 Hz) APCI-MASS (m / z): 643 (M + H) +.

The following compounds (Exes 39 to 43) were obtained according to a manner similar to that of Example 38.

Example 39 7β- (2-phenylacetamido) -3- [4- (2-carboxyethyl) thiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl and potassium NMR (DMSO-d6, d): 2.5- 2.6 (2 H, m), 2.8-3.0 (2 H, m), 3.56 (2 H, s), 3.52 and 3.77 (2 H, ABq, J = 17.3 Hz), 5.26 (1 H, d, J = 5.0 Hz), 5.82 (1 H, dd, J = 5.0 and 8.4 Hz), 6.96 (1 H, s), 7.1-7.5 (16 H, m), 9.24 (1 H, d, J = 8.4 Hz).

EXAMPLE 40 benzhydryl 7β- (2-phenylacetamido) -3- (5-ureidoothiazol-2-yl) thio-3-cephem-4-carboxylate «NMR (DMSO-d6, d): 3.52 (2 H, d, J = 3.8 Hz), 3.57 and 3.85 '5 (2 H, ABq, J = 17.7 Hz), 4.32 (2 H, s), 5.28 (1 H, d, J = 5.0 Hz), 5.83 (1 H, dd , J = 5.0 and 8.4 Hz), 7.00 (1 H, s), 7.1-7.5 (15 H, m), 8.01 (1 H, s), 9.25 (1 H, d, J = 8.4 Hz), 10.75 ( 1 H, sa).

Example 41 7- (2-phenylacetamido) -3- (4-t iocarbamoylmethylthiazol-2 yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 3.53 (2 H, d , J = 3.4 Hz), 3.54 and 3.76 (2 H, ABq, J = 17.9 Hz), 3.98 (2 H, s), 5.24 (1 H, d, J 5 = 5.0 Hz), 5.82 (1 H, dd , J = 5.0 and 8.4 Hz), 6.97 (1 H, s), 7.2-7.5 (15 H, m), 7.61 (1 H, s), 9.26 (1 H, d, J = 8.4 Hz), 9.33 ( 1 H, sa), 9.63 (1 H, sa). APCI-MASS (m / z): 673 (M + H) +. 0 Example 42 Potassium salt of 7β- [2- (2-thienyl) acetamido] -3- [4- (2-carboxyethyl) thiazol-2-yl] thio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO -de, d): 2.5-2.7 (2 H, m), 2.8-3.0 (2 H, m), 5 3.5-3.8 (4 H, m), 5.27 (1 H, d, J = 5.0 Hz), 5.83 (1 H, dd, J = 5.0 and 8.3 Hz), 6.9-7.0 (3 H, m), 7.2-7.5 (12 H, m), 9.28 (1 H, d, J = 8.3 Hz).

Example 43 Potassium salt of 7β- [2- (3-thienyl) acetamido] -3- (4-carboxymethylthiazol-2-yl) thio-3-cef em-4-carboxylic acid benzhydryl NMR (DMSO-de, d) : 3.54 (2 H, s), 3.74 (2 H, s), 3.52 and 3. 75 (2 H, ABq, J = 17.3 Hz), 5.27 (1 H, d, J = 4.9 Hz), 5.83 (1 H, dd, J = 4.9 and 8.4 Hz), 6.9-7.1 (2 H, m) , 7.2-7.7 (13 H, m), 9.23 (1 H, d, J = 8.4 Hz). APCI-MASS (m / z): 664 (M + H) +.

Example 44 To a mixture of benzhydryl 7β- (2-phenylacetamido) -3- (4-thiocarbamoylmethylthiazol-2-yl) thio-3-cephem-4-carboxylate (1.46 g), anisole (1.46 ml) and dichloromethane (4.38) ml) was added trifluoroacetic acid (2.92 ml) at 15 ° C. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran, ethyl acetate and water, and adjusted to pH 7.5 with aqueous sodium hydrogen carbonate. The separated aqueous solution was washed with ethyl acetate, adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate, and * 5 evaporated under reduced pressure. The residue was subjected to preparative HPLC (eluent: buffer solution pH 3 / acetonitrile) to give 7β- (2-phenylacetamido) -3- (4-thiocarbamoylmethylthiazol-2-yl) thio-3-cephem-4-carboxylic acid (62 mg). -0 IR (KBr): 1774, 1660, 1537 cm "1 NMR (DMSO-d6, 8): 3.52 (2 H, d, J = 3.9 Hz), 3.49 and 3.74 (2 H, ABq, J = 17.6 Hz), 3.97 (2 H, s), 5.17 (1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H, m), 7.58 (1 H, s), 9.21 (1 H, d, J = 8.3 Hz), 9.32 5 (1 H, sa), 9.60 (1 H, sa). FAB-MASS (m / z): 507 (M + H) +.

The following compounds (Examples 45 and 46) were obtained according to a manner similar to that 0 of Example 44.

Example 45 7β- (2-phenylacetamido) -3- (4-carboxymethi 1-4,5,6,7-tetrahydrobenzothiazol-2-yl) thio- 3 -ce fem- 4 -carboxylic acid [R, S any of the two, polar] IR (KBr): 1784, 1693, 1666, 1533 cm "1 NMR (DMSO-de, d): 1.3-2.1 (4 H, m), 2.1-2.5 (1 H, m), 2.6-2.9 (3 H, m), 3.0-3.3 (1 H, m), 3.52 (2 H, d, J = 4.1 Hz), 3.40 and 3.72 (2 H, ABq, J = 17.6 Hz), 5.19 1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 4.9 and 8.3 Hz), 7.1-7.4 (5 H, m), 9.19 (1 H, d, J = 8.3 Hz). MASS (m / z): 546 (M + H) +.

EXAMPLE 46 7β- (2-Phenylacetamido) -3- (4-carboxymethyl-4,5,6,7-tetrahydro-2-yl) thio-3-cephem-4-carboxylic acid [R, S any of the two, less polar] IR (KBr): 1781, 1712, 1670, 1533 cm "1 NMR (DMSO-de, d): 1.4-2.1 (4 H, m), 2.1-2.5 (1 H, m), 2.6 -2.9 (3 H, m), 3.0-3.3 (1 H, m), 3.52 (2 H, d, J = 4. 0 Hz), 3.40 and 3.75 (2 H, ABq, J = 17.6 Hz), 5.19 (1 H, d, J = 4.9 Hz), 5.73 (1 H, dd, J = 4.9 and 8.3 Hz9, 7. 1-7.4 (5 H, m), 9.18 (1 H, d, J = 8.3 Hz). FAB-MASS (m / z): 546 (M + H) +.

Example 47 To a solution of 2- (2-mercaptothiazol-4-yl) acetamide (895 mg) in tetrahydrofuran (10.7 ml) and dimethoxyethane (10.7 ml) was added potassium t-butoxide (480 mg) at -10 ° C. , and the solution was stirred at the same temperature for 20 minutes. On the other hand, a solution of benzhydryl 7β- [2- (3-thienyl) acetamido] -3-methanesulfonyloxy-3-cephem-4-carboxylate (2.5 g) in tetrahydrofuran (35 ml) was added to the above solution at -15 ° C. After stirring under ice cooling for 2 hours, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue, and the resulting crystals were collected by filtration to give 7β- [2- (3-thienyl) acetamido] -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl ester (1.64 g) . IR (KBr): 1784, 1666, 1537 c "1 NMR (DMSO-de, d): 3.55 (2 H, s), 3.57 (2 H, s), 3.54 and 3.74 (2 H, ABq, J = 17.7 Hz), 5.26 (1 H, d, J = 5.0 Hz), 5.82 (1 H, dd, J = 5.0 and 8.4 Hz), 6.97 (1 H, s), 7.0-7.1 (2 H, m), 7.2 -7.5 (13 H,), 7.56 (1 H, s), 9.22 (1 H, d, J = 8.4 Hz) APCI-MASS (m / z): 663 (M + H) + The following compounds ( Examples 48 to 5JU were obtained according to a manner similar to that of Example 47.

EXAMPLE 48 7-benzyl-4-carboxylic acid benzyl-3-benzyl-3-benzyl-3-phenylcarbamate (DMSO-de, d): 3.45 (2 H, s), 3.53 (2 H, d, J = 3.8 Hz), 5.20 (1 H, d, J = 4.7 Hz), 5.71 (1 H, dd, J = 4.7 and 8.3 Hz), 6.31 (2 H, sa), 6.87 ( 1 H, s), 6.93 (1 H, s), 7.2-7.6 (15 H, m), 9.13 (1 H, d, J = 8.3 Hz).

Example 49 7β- (2-phenylacetamido] -3- [4- (2-carbamoylethyl) thiazol-2-yl] -3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 2.4-2.5 (2 H, m), 2.92 (2 H, t, J = 7.9 Hz), 3.53 (2 H, d, J = 3.3 Hz), 3.52 and 3.76 (2 H, ABq, J = 17.7 Hz), 5.26 (1 H , d, J = 5.0 Hz), 5.82 (1 H, dd, J = 5.0 and 8.4 Hz), 6.78 (1 H, sa), .97 (1 H, s), 7.2-7.5 (17 H, m) , 9.24 (1 H, d, J = 8.4 Hz).

EXAMPLE 50 Benzyl-4-benzyl-4-carboxylic acid benzyl amide-NMR (DMSO-de, d): 2.71 (2 H) 50-7- (2-phenylacetamido) -3- [4- (2-methoxycarbonylethyl) -thiazol-2-yl] -3-cephem-4-carboxylate , t, J = 7.3 Hz), 2.97 (2 H, t, J = "7.3 Hz), 3.53 (2 H, d, J = 3.6 Hz), 3.58 (3 H, s), 3.54 and 3.76 (2 H , ABq, J = 17.7 Hz), 5.26 (1 H, d, J = 4.9 Hz), 5.82 (1 H, dd, J = 4.9 and 8.4 Hz), 6.96 (1 H, s), 7.1-7.5 (15 H, m), 7.48 (1 H, s), 9.24 (1 H, d, J = 8.4 Hz).

Example 51 7β- [2- (2-thienyl) acetamido) -3- (4-carbamoylmethylthiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl IR (KBr): 1780, 1666, 1537 cm "1 NMR (DMSO-de, d): 3.57 (2 H, s), 3.76 (2 H, s), 3.52 and 3. 78 (2 H, ABq, J = 17.5 Hz), 5.27 (1 H, d, J = 5.0 Hz), 5.83 (1 H, dd, J = 5.0 and 8.3 Hz), 6.9-7.1 (4 H, m) , 7.2-7.5 (12 H, m), 7.55 (1 H, s), 9.28 (1 H, d, J = 8. 3 Hz). APCI-MASS (m / z): 663 (M + H) +.

Example 52 Phosphorus oxychloride (473 μl) was added dropwise to a mixture of N, N-dimethylformamide (388 μl) and ethyl acetate (1 ml) under ice-cooling. After being stirred for 10 minutes at the same temperature, the mixture was cooled until a precipitate appeared. Tetrahydrofuran was added to the suspension (17 ml). The suspension was stirred at the same temperature for 30 minutes. To the suspension was added 2- (5-tert-butoxycarbonylamino- 1,2,4-thiadiazol-3-yl) acetic acid (1.0 g). The mixture was stirred at the same temperature for 30 minutes, to give an activated acid solution. On the other hand, to a suspension of 7β-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid (1.16 g) in tetrahydrofuran (17 ml) was added N-trimethylsilylacetamide (3.7 g) The suspension was stirred at 20-40 ° C for 40 minutes to give a clear solution To the solution was added the activated acid solution prepared above, a - 20 ° C. The mixture was stirred at -20-5 ° C. for 40 minutes.The reaction mixture was added to a mixture of ethyl acetate (100 ml), sodium hydrogen carbonate (1.59 g) and water (100 ml). ml) To the separated aqueous solution was added ethyl acetate (100 ml). The mixture was adjusted to pH 2 with 1N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- [2- (5-tert-buto-carboni-1-amino-1, 2,4-thiadiazol-3-yl) -acetamido-3- (5-methyl-1, 3, 4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid (1.17 g). NMR (DMSO-d6, d): 1.50 (9 H, s), 2.72 (3 H, s), 3.54 and 3.86 (2 H, ABq, J = 17 Hz), 3.70 and 3.79 (2 H, ABq, J = 15 Hz), 5.24 (1 H, d, J = 5 Hz), 5.80 (1 H, dd, J = 5 and 8 Hz), 9.22 (1 H, d, J = 8 Hz), 12.29 (1 H , sa). FAB-MASS (m / z): 572.0 The following compounds (Examples 53 to 5_6) were obtained according to a manner similar to that of Example 52).

EXAMPLE 53 7β- [2- (5-Chloro-2-formylaminothiazol-4-yl) acetamido] -3- (5-methi 1-1, 3, 4-thiadiazol-2-yl) thio-3 -ce fem acid - 4-carboxylic NMR (DMSO-de, d): 2.72 (3 H, s), 3.54 and 3.85 (2 H, ABq, J = 17 Hz), 3.60 (2 H, s), 5.23 (1 H, d , J = 5 Hz), 5.79 (1 H, dd, J = 5 Hz and 8 Hz), 8.49 (1 H, s), 9.20 (1 H, d, J = 8 Hz), 12.52 (1 H, sa ).

Example 54 7- (1-Phenyl-1-cyclopropanecarboxamido) -3- (5-methyl-1, 3, 4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid NMR acid (DMSO-de) , d): 1.0-1.2 (2 H, m), 1.3-1.5 (2 H, m), 2. 72 (3 H, s), 3.51 and 3.79 (2 H, ABq, J = 17 Hz), 5.18 (1 H, d, J = 5 Hz), 5.68 (1 H, dd, J = 5 and 8 Hz), 7.2-7.4 (5 H, m), 7.74 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 475.1 EXAMPLE 55 7β Acid [(Z) - (2- (2-t-Butoxycarbonylaminothiazol-4-yl) -2-pentenoi lamino] -3- (5-methyl-1,3,4-thiadiazol-2-yl) ti -o-3-cephem-4-carboyl NMR (DMSO-de, d): 1.02 (3 H, t, J = 6 Hz), 2.2-2.4 (2 H, m), 2.72 (3 H, s) , 3.54 and 3.83 (2 H, ABq, J = 17 Hz), . 24 (1 H, d, J = 5 Hz), 5.80 (1 H, dd, J = 5 and 8 Hz), 6. 53 (1 H, t, J = 7 Hz), 7.04 (1 H, s), 8.87 (1 H, d, J = 8 Hz), 11.57 (1 H, s).

Example 56 7β [2- (4-fluorophenyl) acetamido] -3 - [(Z) -2- (3-pyridyl) -vinylthio] -3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 3.50 and 3.56 (2 H, ABq, J = 12 Hz), 3.82 and 4.09 (2 H, ABq, J = 18 Hz), 5.20 (1 H, d, J = 5 Hz), 5.77 (1 H, dd, J = 5 and 8 Hz), 6.75 (1 H, d, J = 11 Hz), 6.82 (1 H, d, J = 11 Hz), 6.93 (1 H, s), 7.1-7.5 (15 H, m), 7.7-7.8 (1 H, m), 8.4-8.5 (1 H, m), 8.60 (1 H, m), 9.21 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 638.1 Example 57 To a solution of 4-carboxymethyl-2-mercaptothiazole (719 mg) in a mixture of tetrahydrofuran (14 ml) and 1,2-dimethoxyethane (14 ml) was added potassium t-butoxide (768 mg) at room temperature. ice cooling with stirring, and the mixture was stirred at the same temperature for 1 hour. A solution of benzydryl 7β- [2- (2-thienyl) acetamido] -3-methanesul fonyloxy-3-cephem-4-carboxylate (2.0 g) in a mixture of tetrahydrofuran (10 ml) and 1, 2- dimethoxyethane (10 ml) was added to the potassium salt mixture obtained at the same temperature, and the mixture was stirred at -5-0 ° C for 2 hours. The reaction mixture was poured into an ice-water mixture (100 ml) and ethyl acetate (150 ml). The mixture was adjusted to pH 7.0 with 1N sodium hydroxide solution. The separated organic layer was washed with 1 N hydrochloric acid and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with a mixture of diethyl ether and ethyl acetate (2: 1) to give 7β- [2- (2-thienyl) acetamido] -3- (4-car or imethyl-thiazol-2-yl) thio. -3-cephem-4-carboxylate benzhydryl (687 mg). NMR (DMSO-de, d): 3.57 and 3.79 (2 H, ABq, J = 18 Hz), 3.7-3.8 (4 H, m), 5.27 (1 H, d, J = 5 Hz), 5.83 (1 H, dd, J = 5 and 8 Hz), 6.9-7.0 (1 H, m), 6.93 (1 H, m), 6.97 (1 H, s), 7.2-7.4 (11 H, m), 7.61 ( 1 H, s), 9.27 (1 H, d, J = 8 Hz).

The following compounds (Examples 58 to 62) were obtained according to a manner similar to that of Example 57.

Example 58 7β- (2-phenylacetamido) - (3-ethoxycarbonylmethyl-1,2,4-triazol-5-yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 1.18 (3 H, t, J = 7 Hz), 3.41 and 3.57 (2 H, ABq, J = 17 Hz), 3.92 (2 H, sa), 3.92 (2 H, sa), 4.11 (2 H, ABq, J = 7 Hz), 5.23 (1 H, d, J = 5 Hz), 5.75 (1 H, dd, J = 5 and 8 Hz), 6.93 (1 H, s), 7.2-7.6 (15 H, m), 9.17 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 670.1.

Example 59 7β- (2-phenylacetamido) -3- (3-carboxymethyl-1,2,4-triazol-5-yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-d6, d): 3.3 -3.6 (4 H, m), 3.78 (2 H, s), 5.23 (1 H, d, J = 5 Hz), 5.75 (1 H, dd, J = 5 and 8 Hz), 6.93 (1 H, s), 7.2-7.5 (5 H, m), 12.8 (1 H, sa), 14.1 (1 H, sa). FAB-MASS (m / z): 642.0 Example 60 7β- (2-phenylacetamido) -3- (2-carboxymethyl-1,3,4-thiadia-zol-5-yl) thio-3-cephem-4-carboxylate of benzhydryl-NMR (DMSO-de, d): 3.3-3.7 (4 H, m), 4.24 (2 H, s), 5.28 (1 H, d, J = 5 Hz), 5.87 (1 H, dd, J = 5 and 8 Hz), 6.95 (1 H, s), 7.2-7.5 (15 H,), 9.29 (1 H, d, J = 5 Hz). FAB-MASS (m / z): 658.6 Example 61 7β- [2- (2-thienyl) acetamido) -3- [4- (2-carbamoylethyl) -thiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d) ): 2.44 (2 H, t, J = 7 Hz), 2.91 (2 H, t, J = 7 Hz), 3.52 and 3.78 (2 H, ABq, J = 14 Hz), 3.76 (2 H, s) , 5.28 (1 H, d, J = 5 Hz 9, 5.86 (1 H, dd, J = 5 and 8 Hz), 6.81 (1 H, sa), 6.9-7.0 (3 H, m), 7.2-7.5 ( 13 H, m), 9.29 (1 H, d, J = 5 Hz) FAB-MASS (m / z): 676.9 Example 62 7β- [2- (3-ti-enyl) acetamido] -3- [4- (2-carbamoylethyl) -thiazol-2-yl) thio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 2.44 (2 H, t, J = 7 Hz), 2.92 (2 H, t, J = 7 Hz), 3.55 (2 H, s), 3.51 and 3.77 (2 H, ABq, J = 14 Hz ), 5.22 (1 H, d, J = 5 Hz), 5.84 (1 H, dd, J = 5 and 8 Hz), 6.81 (1 H, sa), 6.97 (1 H, s), 7.0-7.1 ( 1 H,), 7.2-7.5 (14 H, m), 9.23 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 676.8 Example 63 To a solution of 3-benzoyl thiomet ilpyridine (950 mg) in dimethoxyethane (8 ml) was added in 28% sodium methoxide methanol solution under ice cooling. The mixture was stirred for 30 minutes at 5-8 ° C. The mixture was added dropwise to a solution of 7β- (2-phenylacetamido) -3-methansulphon-loxy-3-cephem-4-benzhydrylcarboxylate in dimethoxyethane (10 ml) and N, N-dimethylformamide (8 ml) at -65 ° C for 5 minutes. The mixture was stirred at -65 ° C for 60 minutes. To the reaction mixture was added the cooled buffer solution (pH 4, 100 ml) and ethyl acetate (100 ml), and adjusted to pH 6.7 with 1 N sodium hydroxide solution. The separated organic layer was washed with water (100 ml x 3) and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- (2-phenylacetamido) -3- (3-pyridyl) methylthio-3-cephem-4-carboxylate benzhydryl (1.83 g). NMR (DMSO-de, d): 3.51 and 3.59 (2 H, ABq, J = 14 Hz), 3.93 and 3.83 (2 H, ABq, J = 18 Hz), 4.15 and 4.23 (2 H, ABq, J = 14 Hz), 5.16 (1 H, d, J = 5 Hz), 5.68 (1 H, dd, J = 5 and 8 Hz), 6.85 (1 H, s), 7.2-7.4 (14 H, m), 7.4-7.5 (2 H, m), 7.6-7.7 (1 H, m), 8.4-8.5 (2 H, m), 9.18 (1 H, d, J = 8 Hz). "5 FAB-MASS (m / z): 608.1.

The following compounds (Examples 64 to 69) were obtained according to a manner similar to that of Example 63. Example 64 i 7- (2-phenylacetamido) -3- [2- (1-tritylpyrazol-4-yl) - ethylthio] -3-cephem-4-carboxylic acid benzhydryl NMR (DMS0-d6, d): 2.5-2.7 (2 H, m), 2.9-3.1 (2 H, m), 3.59 and 3.51 (2 H, ABq, J = 14 Hz), 3.81 (2 H, sa), 5.12 (1 H, d, J = 5 Hz), 5.66 (1 H, dd, J = 5 and 8 Hz), 6.85 (1 H, s ), 7.0-7.6 (32 H, m), 9.16 (1 H, d, J = 8 Hz).

Example 65 0 7β- (2-phenyl acetamido) -3- (1, 2, 3-thiadiazol-5-yl) methylthio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 3.50 and 3.58 (2 H, ABq, J = 14 Hz), 3.79 and 3.89 (2 H, ABq, J = 17 Hz), 4.66 (2 H, s), 5.18 (1 H, d, J = 5 Hz), 5.71 ( 1 H, dd, J = 5 and 8 Hz), 6.87 (1 H, s), 7.2-7.5 (15 H, m), 8.81 (1 H, s), 9.18 (1 H, d, J = 8 Hz ). FAB-MASS (m / z): 615.0 Example 66 7- (2-phenylacetamido) -3- [2- (3-pyridyl) ethylthio] -3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d): 2.7-2.9 (2 H, m) , 3.1-3.2 (2 H, m), 3. 51 and 3.60 (2 H, ABq, J = 14 Hz), 3.87 (2 H, s), 5.16 (1 H, d, J = 5 Hz), 5.68 (1 H, dd, J = 5 and 8 Hz) 6.88 (1 H, s), 7.2-7.7 (17 H, m), 8.4.8.5 (2 H, m), 9.16 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 622.1 Example 67 7β- [2- (2-thienyl) acetamido] -3- (1, 2, 3-thiadiazol-5-yl) -methylthio-3-cephem-4-carboxylic acid benzhydryl NMR (DMSO-de, d) : 3.77 (2 H, s), 3.81 and 3.91 (2 H, ABq, J = 14 Hz), 4.66 (2 H, s), 5.20 (1 H, d, J = 5 Hz), 5.72 (1 H, dd, J = 5 and 8 Hz), 6.8-7.0 (3 H, m), 7.2-7.5 (11 H, m), 8.81 (1 H, s), 9.20 (1 H, d, J = 8 Hz) . FAB-MASS (m / z): 620.9 Example 68 7β- (2-phenylacetamido) -3- (4-carbamoylmethylthiazol-2-yl) thiomethylthio-3-cephem-4-carboxylate of benzhydryl-NMR (DMSO-de, d): 3.4-3.9 (8 H,), 5.26 (1 H, d, J = 5 Hz), 5.83 (1 H, dd, J = 5 and 8 Hz), 6.97 (1 H, s), 7.02 ( 1 H, sa), 7.2-7.6 (16 H, m), 7.56 (1 H, s), 9.20 (1 H, d, J = 8 Hz).

Example 69 7β - [(Z) -2- (2-cyanovinylthio) acetamido] -3- [2- (1-tritylpi-razol-4-yl) ethylthio] -3-cephem-4-carboxylic acid benzhydryl NMR (DMSO -de, d): 2.5-2.7 (2 H, m), 2.9-3.1 (2 H, m), 3.75 (2 H, s), 3.82 (2 H, sa), 5.16 (1 H, d, J = 5 Hz), 5.68 (1 H, dd, J = 5 and 8 Hz), 5.73 (1 H, d, J = 10 Hz), 6.86 (1 H, s), 6.9-7.6 (27 H, m) , 7.68 (1 H, d, J = 10 Hz), 9.25 (1 H, d, J = 8 Hz).

Example 70 To a solution of 7β- [2- (2-formylaminothiazol-4-yl) acetamido] -3- (5-methyl 1-1, 3, 4-thiadiazol-2-yl) thio] -3-cephem-4-carboxylic acid benzhydryl (1.2 g) in a mixture of dichloromethane (3.6 ml) and anisole (1.2 ml) was added trifluoroacetic acid (2.4 ml) under ice cooling. The mixture was stirred at the same temperature for 45 minutes. The reaction mixture was taken up in diisopropyl ether (80 ml) and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (40 ml), tetrahydrofuran (20 ml), and ethyl acetate (40 ml). To the separated aqueous solution were added ethyl acetate (40 ml) and tetrahydrofuran (20 ml). The mixture was adjusted to pH 1.8 with 1 N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β- [2- (2-formyl inot-aiazol-4-yl) -acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) acid. ) thio] -3-cephem-4-carboxylic acid (490 mg). NMR (DMSO-de, d): 2.72 (3 H, s), 3.43 and 3.85 (2 H, ABq, J = 17 Hz), 3.60 (2 H, s), 5.23 (1 H, d, J = 5 Hz9, 5.80- (1 H, dd, J = 5 and 8 Hz), 6.95 (1 H, s), 8.45 (1 H, s), 9.11 (1 H, d, J = 8 Hz), 12.22 (1 H, sa 9. FAB-MASS (m / z): 499.0 The following compounds (Examples 71 to 8_0) were obtained according to a manner similar to that of Example 70.

EXAMPLE 71 7β- [2- (2-Acetylaminothiazol-4-yl) acetamido] -3- (5-methyl-1, 3, 4-thiadiazol-2-yl) thio] -3-cephem-4-carboxylic NMR (DMSO-de, d): 2.11 (3 H, s), 2.72 (3 H, s), 3.44 and 3.84 (2 H, ABq, J = 17 Hz), 3.58 (2 H, s), 5.22 (1 H, d, J = 5 Hz), 5.79 (1 H, dd, J = 5 and 8 Hz), 6.86 (1 H, s), 9.09 (1 H, d, J = 8 Hz), 12.09 (1 H , s). FAB-MASS (m / z): 513 Example 72 7β- [2- (2-Thienyl) acetamido] -3- (4-carboxymethyl-thiazol-2-yl) thio] -3-cephem-4-carboxylic acid IR (Nujol): 3300, 1780, 1695 , 1640, 1530, 1240 cm "1 NMR (DMS0-ds, d): 3.48 and 3.75 (2 H, ABq, J = 18 Hz), 3.7-3.8 (4 H, m), 5.21 (1 H, d, J = 5 Hz), 5.75 (1 H, dd, J = 5 and 8 Hz), 6.9-7.0 (1 H, m), 6.92 (1 H, s), 7.3-7.4 (1 H, m), 7.59 (1 H, s), 9.23 (1 H, d, J = 8 Hz) FAB-MASS (m / z): 498.0.

Example 73 7β- (2-Phenylacetamido) -3- (5-ethoxycarbonylmethyl-1,2,4-triazol-3-yl) thio-3-cephem-4-carboxylic acid NMR (DMS0-d6, d): 1.19 ( 3 H, t, J = 7 Hz), 3.3-3.6 (4 H, m), 3.90 (2 H, sa), 4.12 (2 H, q, J = 7 Hz), 5.16 (1 H, d, J = 5 Hz), 5.65 (1 H, dd, J = 5 and 8 Hz), 7.2-7.3 (5 H, m), 9.12 (1 H, d, J = 8 Hz), 13.7 (1 H, sa) , 14.3 (1 H, sa). FAB-MASS (m / z): 504.0.

Example 74 7β- (2-phenylacetamido) -3- [(Z) -2- (3-pyridyl) vinyl-thio] -3-cef m-4-carboxylic acid FAB-MASS (m / z): 454.0.

Example 75 7β- [2- (4-Fluorophenyl) acetamido]) -3 - [(Z) -2- (3-pyridyl) vinylthio] -3-cephem-4-carboxylic acid NMR (DMSO-de, d) : 3.50 and 3.56 (2 H, ABq, J = 14 Hz9, 3.73 and 4.07 (2 H, AB, J = 18 Hz), 5.15 (1 H, d, J = 5 Hz), 5.70 (1 H, dd, J = 5 and 8 Hz), 6.78 (1 H, d, J = 11 Hz), 6.8 (1 H, d, J = 11 Hz), 7.0-7.2 (2 H, m), 7.2-7.4 (2 H, m), 7.4-7.5 (1 H, m), 7.8-7.9 (1 H, m), 8.4-8.5 (1 H, m), 8.65 (1 H, m), 9.17 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 472.1.

Example 76 7β- (2-phenylacetamido]) -3- (3-pyridyl) methylthio-3-cephem-4-carboxylic acid IR (KBr): 3284, 3057, 1784, 1757, 1666, 1606, 1537, 1379, 1348 , 1242 c "1 NMR (DMSO-de, d): 3.49 and 3.58 (2 H, ABq, J = 14 Hz), 3.79 (2 H, s), 4.13 and 4.21 (2 H, ABq, J = 12 Hz ), 5.08"5 (1 H, d, J = 5 Hz), 5.61 (1 H, dd, J = 5 and 8 Hz), 7.1- 7.4 (5 H, m), 7.3-7.5 (1 H, m ), 7.7-7.9 (1 H, m), 8.4-6.6 (2 H, m), 9.15 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 441.9. -10 Example 77 7β- [2- (2-Thienyl) acetamido] -3- [4- (2-carbamoyl-ethyl) thiazol-2-yl] thio- 3 -ce fem- 4 -carboxylic acid (Nujol) ): 3405, 3280, 1774, 1689, 1664, 1535, 1433, 1412, 1365, 1282, 1242 cm "1 15 NMR (DMSO-de, d): 2.43 (2 H, t, J = 7 Hz), 2.90 (2 H, t, J = 7 Hz), 3.47 and 3.75 (2 H, ABq, J = 17 Hz), 3.76 (2 H, s), 5.23 (1 H, d, J = 5 Hz), 5.75 ( 1 H, dd, J = 5 and 8 Hz), 6.80 (1 H, sa), 6.9-7.0 (2 H, m), 7.3-7.4 (3 H, m), 9.25 (1 H, d, J = 8 Hz) 20 FAB-MASS (m / z): 510.8.

Example 78 7β- [2- (3-Thienyl) acetamido] -3- [4- (2-carbamoyl-ethyl) thiazol-2-yl] thio- 3 -ce fem- 4 -carboxylic acid 25 IR (KBr) : 3406, 3294, 1772, 1657, 1535, 1365, 1242 cm "1 NMR (DMSO-ds, d): 2.43 (2 H, t, J = 7 Hz), 2.90 (2 H, t, J = 7 Hz), 3.47 and 3.75 (2 H, ABq, J = 18 Hz), 3.54 (2 H, s), 5.22 (1 H, d, J = 5 Hz), 5.75 (1 H, dd, J- = 5 y 8 Hz), 6.80 (1 H, sa), 7.0-7.1 (1 H, m), 7.2-7.3 (1 H, * 5 m), 7.34 (1 H, sa), 7.4-7.5 (2 H, m), 9.18 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 510.8.

Example 79 -10 7β- (2-phenylacetamido) -3- (1, 2, 3-thiadiazol-5-yl) -methylthio-3-cephem-4-carboxylic acid IR (KBr): 3440, 3890, 3340, 1770, 1680, 1535, 1360, 1240 c "1 NMR (DMSO-de, d): 3.48 and 3.57 (2 H, ABq, J = 14 Hz), 15 3.76 (2 H, s), 4.67 (2 H, s), 5.10 (1 H, d, J = 5 Hz), . 63 (1 H, dd, J = 5 and 8 Hz), 7.2-7.3 (5 H, m), 8.85 (1 H, s), 9.16 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 448.9.

Example 80 7β- (2-Phenylacetamido] -3- [(E) -2- (1-benzylcarbonylpyrazol-4-yl) vinylthio] -3-cephem-4-carboxylic acid IR (Nujol): 3250, 1760, 1690, 1650, 1520, 1230 cm "1 NMR (DMSO-de, d): 3.49 and 3.59 (2 H, ABq, J = 14 Hz), 3.70 and 3.96 (2 H, ABq, J = 17 Hz), 4.45 (2 H, s), 5.15 (1 H, d, J = 5 Hz), 5.65 (1 H, dd, J = 5 and 8 Hz ), 6.73 (1 H, d, J = 15 Hz), 7.16 (1 H, d, J = 15 Hz), 7.2-7.4 (10 H, m), 8.20 (1 H, s), 8.53 (1 H , s), 9.14 (1-H, d, J = 8 Hz). FAB-MASS (m / z): 561.3 EXAMPLE 81 To a solution of benzhydryl 7β- (2-phenylacetamido) -3- (3-carboxymethyl-1,2,4-triazol-5-yl) thio-3-cephem-4-carboxylic acid α-toyl ester (370 mg ) in a mixture of dichloromethane (1.2 ml) and anisole (0.4 ml) was added trifluoroacetic acid (0.8 ml) under ice cooling. The mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into diisopropyl ether (30 ml), and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (58 mg / 30 ml), tetrahydrofuran (10 ml) and ethyl acetate (30 ml). To the separated aqueous layer were added tetrahydrofuran (10 ml) and ethyl acetate (30 ml), adjusted to pH 2.0 with 1 N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give the crude product (190 mg). The crude product (175 mg) was dissolved in a mixture of aqueous sodium bicarbonate (62 mg / 10 ml), purified by high pressure liquid chromatography (CLAP) (R-ODS-C-15, YMC packaging) eluting * 5 with 20% acetoni trilo-phosphate buffer (pH 3.0). The solution was concentrated in vacuo. To the resulting solution was added tetrahydrofuran (10 ml) and ethyl acetate (40 ml) and adjusted to pH 2.2 with 1N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over sodium sulfate, and dried. magnesium, and concentrated in vacuo. The residue was triturated with isopropyl ether to give 7β- (2-phenylacetamido) -3- (5-carboxymethyl-1,2,4-triazol-3-yl) -thio-3-cephem-4-carboxylic acid (25.7 mg). 5 NMR (DMSO-de, d): 3.3-3.6 (4 H, m), 3.81 (2 H, sa), 5.16 (1 H, d, J = 5 Hz), 5.65 (1 H, dd, J = 5 and 8 Hz), 7.1- 7.3 (5 H, m), 9.12 (1 H, d, J = 8 Hz), 14.2 (1 H, sa). FAB-MASS (m / z): 476.0.

The following compounds (Examples 82 to 8_4_) were obtained according to the manner similar to that of Example 81.

Example 82 7β- (2-phenylacetamido) -3- (1-carboxymethyl-1, 2,3,4-tetrazol-5-yl) thio-3-cephem-4-carboxylic acid NMR (DMSO-de, d) ): 3.3-3.7 (4 H,), 5.19 (1 H, d, J = 5 Hz), 5.40 and 5.51 (2 H, AB, J = 18 Hz), 5.74 (1 H, dd, J = 5 y 8 Hz), 7.2-7.3 (5 H, m), 9.13 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 476.9.

Example 83 7β- (2-Phenylacetamido) -3- (5-carboxymethyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid NMR (DMSO-de, d): 3.48 and 3.57 (2 H, ABq, J = 14 Hz), 3.54 and 3.87 (2 H, ABq, J = 18 Hz), 4.24 (2 H, s), 5.23 (1 H, d, J = 5 Hz), 5.29 (1 H, dd, J = 5 and 8 Hz), 7.2-7.3 (1 H, m), 9.24 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 492.8.

EXAMPLE 84 7β- [2- (2-Thienyl) acetamido] -3- (1, 2, 3-thiadiazol-5-yl) methylthio-3-cephem-4-carboxylic acid IR (KBr): 3380, 1770, 1680, 1540, 1510, 1370, 1240 cm "1 NMR (DMSO-de, d): 3.76 (2 H, sa), 3.76 (2 H, sa), 4.62 (2 H, s), 5.12 (1 H, d, J = 5 Hz), 5.64 (1 H , dd, J = 5 and 8 Hz), 6.9-7.0 (2 H, m), 7.3-7.4 (1 H, m), 8.85 (1 H, s), 9.17 (1 H, d, J = 8 Hz ).

FAB-MASS (m / z) 454.57 Example 85 To a solution of benzhydryl 7β- (2-phenylacetamido) -3- [2- "5- (1-tritylpyrazol-4-yl) ethylthio] -3-cephem-4-carboxylate (930 mg) in a mixture of dichloromethane (3 ml) and anisole (1 ml) was added trifluoroacetic acid (2 ml) under ice cooling.The mixture was stirred at room temperature for 1 hour. was poured into diisopropyl ether (100 ml). The precipitate was collected by filtration. The precipitate was added to 90% formic acid (4 ml) and stirred for 15 minutes at room temperature. The reaction mixture was poured into a mixture of ethyl acetate (100 ml) and ice-water (50 ml). To the separated organic layer buffer solution (pH 6.86, 100 ml) was added, adjusted to pH 7 with sodium bicarbonate. To the separated aqueous layer was added ethyl acetate (60 ml) and tetrahydrofuran (30 ml), adjusted to pH 2.5 with N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- (2-phenylacetamido) -3- [2-pyrazol-4-yl) ethylthio] -3-cephem-4-carboxylic acid (275 mg).

IR (KBr): 3400, 3270, 1780, 1660, 1540, 1360, 1290, 1240 cm "1 NMR (DMSO-de, d): 2.6-2.7 (2 H, m), 3.00 (2 H, t, - J = 7 Hz), 3.49 and 3.58 (2 H, ABq, J = 14 Hz), 3.72 and 3.81 (2 H, ABq, J = 17 Hz), 5.10 (1 H, d, J = 5 Hz), 5.60 (1 H, dd, J = 5 and 8 Hz), 7.2-7.3 (5 H,), 7.47 (2 H, s), 9.14 (1 H, d, J = 8 Hz), 13.0 (1 H, sa ).

The following compound was obtained according to a manner similar to that of Example 85.

Example 86 7β - [(Z) -2- (2-Cyanovinylthio) acetamido] -3- [2-pyrazol-4-yl) ethylthio] -3-cephem-4-carboxylic acid NMR (DMSO-de, d) : 2.6-2.7 (2 H, m), 2.9-3.1 (2 H, m), 3.70 and 3.82 (2 H, ABq, J = 18 Hz), 3.74 (2 H, s), 5.14 (1 H, d , J = 5 Hz), 5.61 (1 H, dd, J = 5 and 8 Hz), 5.73 (1 H, d, J = 10 Hz), 7.47 (2 H, s), 7.67 (1 H, d, J = 10 Hz), 9.23 (1 H, d, J = 8 Hz), 13.0 (1 H, sa). FAB-MASS (m / z): 451.9.

Example 87 To a solution of 7β- [2- (5-tert-butoxycarbonylamino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methi 1-1,3,4-thiadiazole- 2-yl) thio-3-cephem-4-carboxylic acid (800 mg) in dichloromethane (2.4 ml) was added trifluoroacetic acid (10.4 ml). The mixture was stirred for 30 minutes at room temperature. The reaction mixture was poured into diisopropyl ether (150 ml). The precipitate was collected by filtration, and dried. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (212 mg / 30 ml) and tetrahydrofuran (10 ml). The solution was washed with ethyl acetate (30 ml). To the aqueous layer was added a mixture of tetrahydrofuran (15 ml) and ethyl acetate (45 ml), and it was adjusted to pH 2 with 1 N hydrochloric acid. The organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give 7β- [2- (5-amino-1,2,4-thiadiazol-3-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazole-2) -yl) thio-3-cephem-4-carboxylic acid (490 mg). NMR (DMSO-de, d): 2.81 (3 H, s), 3.59 and 3.67 (2 H, ABq, J = 17 Hz), 3.61 and 3.93 (2 H, ABq, J = 15 Hz), 5.32 (1 H, d, J = 5 Hz), 5.88 (1 H, dd, J = 5 and 8 Hz), 7.97 (2 H, sa), 9.22 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 471.9.

The following compound was obtained according to a manner similar to that of Example 87.

EXAMPLE 88 7β- [(Z) -2- (2-aminothiazol-4-yl) -pentenoi lamino] -3- (5-methi 1-1, 3,4-thiadiazol-2-yl) thio- 3 - acid cefem-4-carboxylic IR (KBr): 3410, 3110, 2970, 1780, 1620, 1520, 1400, 1320, 1260, 1200 cm "1 NMR (DMSO-de, d): 1.01 (3 H, t, J = 7 Hz), 2.34 (2 H, dq, J = 7 and 7 Hz), 3.53 and 3.83 (2 H, ABq, J = • 18 Hz), 5.26 (1 H, d, J = 5 Hz), 5.86 ( 1 H, dd, J = 5 and 8 Hz), 6.49 (1 H, s), 6.56 (1 H, t, J = 7 Hz), 7.13 (2 H, sa), 9.13 (1 H, d, J = 8 Hz).

Example 89 To a solution of 7-amino-3- (pyrazol-4-yl) methylthio-3-cephem-4-carboxylic acid (625 mg) in dichloromethane (6 ml) was added monotrimethylsilyl-acetamide (2.625 g) and chloride of trimethylsilyl (0.05 ml), then the solution was stirred under reflux for 1 hour to give a solution containing the silylated cephem (Solution 1) To a solution of R- (-) -mandelic acid (304 mg), N, N-dimethylaminopyridine (catalytic amount) and pyridine (0.33 ml) in dichloromethane (4 ml) was added trimethylsilyl chloride (0.52 ml) and stirred at room temperature for 1 hour. N, N-dimethylformamide (2 drops) and oxalyl chloride (0.18 ml) were successively added to the solution at 0 ° C, and stirred at the same temperature for 1 hour, and at room temperature for 30 minutes. Solution 1 was added to the solution obtained at 0 ° C, and stirred for 2 hours at 0 ° C. To the obtained solution was added a solution of citric acid (423 mg) in methanol (50 ml), and the mixture it was stirred at 0 ° C for 30 minutes. The reaction mixture was quenched with water (100 ml), adjusted to pH 7.2-7.5 with sodium hydrogen carbonate, and washed with ethyl acetate (100 ml). The aqueous layer was adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with a mixture of ethyl acetate and tetrahydrofuran (10: 1) (x3). The combined extracts were washed with water and saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was crystallized from ethyl acetate and diethyl ether, and purified by preparative HPLC (column, YMC P-ODS-15C and Gard Gel, mobile phase phosphate buffer solution (pH 6.0): acetonitrile = 85:15). The eluate obtained was adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with a mixture of ethyl acetate and tetrahydrofuran (10: 1) (x3). The combined extracts were washed with saline, dried over magnesium sulfate, and evaporated under reduced pressure. The residue was precipitated from chloroform, methanol and isopropyl ether to give 7β - [(R) -2-hydroxy-2-phenylacetamido] -3- (pyrazol-4-yl) methylthio-3-cephem-4-carboxylic acid ( 60.5 mg) as a powder. IR (KBr): 1770, 1680 cm "1 NMR (DMSO-d6, d): 3.76 (3 H, s), 4.01 (2 H, s), 5.06-5.11 (2 H, m), 5.59 (1 H , dd, J = 4.7 and 8.8 Hz), 6.15 (1 H, d, J = 5.5 Hz), 7.20-7.47 (5 H,), 7.55 (2 H, s), 8.77 (1 H, d, J = 8.9 Hz.) FAB-MASS (m / z): 447 (M + H) +.

The following compound was obtained according to a manner similar to that of Example 89.

Example 90 7β- [(S) -2-Hydroxy-2-phenylacetamido] -3- (pyrazol-4-yl) ethylthio-3-cephem-4-carboxylic acid IR (KBr): 1770, 1678 cm "1 NMR (DMS0-d6, d): 3.80 (2 H, s), 4.02 (2 H, s), 5.04- 5.10 (2 H, m), 5.54 (1 H, dd, J = 4.6 and 8.7 Hz), 7.20 -7.46 (5 H, m), 7.56 (2 H, s), 8.67 (1 H, d, J = 8.7 Hz). FAB-MASS (m / z): 447 (M + H) +.

Example 91 To a solution of benzhydryl 7β-2- (phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) methylthio-3-cephem-4-carboxylate (1.0 g) in dichloromethane (20 ml) and N , N-dimethylformamide (20 ml) were added 1-hydroxy-benzotriazole (247 mg), WSC-HC1 (349 mg) and 2 M methylamine in solution in tetrahydrofuran (0.91 ml) at room temperature. After stirring at room temperature for 2 hours, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution (x3), dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue, and the resulting crystals were collected by filtration to give 7β- (2-phenyl-acetamido) -3- [4- (N-methemocarbamoylmethyl) thiazol-2-yl] thio-3-cephem Benzhydryl-4-carboxylate (186 mg). NMR (DMSO-de, d): 2.59 (3 H, d, J = 4.6 Hz), 3.53 (2 H, d, J = 3.7 Hz), 3.58 (2 H, s), 3.48 and 3.77 (2 H, ABq, J = 17.7 Hz9, 5.25 (1 H, d, J = 5.0 Hz), 5.81 (1 H, dd, J = 5.0 and 8.5 Hz), 6.97 (1 H, s), 7.2-7.5 (15 H, m), 7.55 (1 H, s), 7.92 (1 H, m), 9.24 (1 H, d, J = 8.5 Hz).

Example 92 To a solution of 7β-2- (phenylacetamido) -3- (4-carboxymethyl thiazol-2-yl) thio-3-cephem-4-carboxylate benzhydryl (500 mg) in N, N-dimethyl formamide ( 10 ml) were added 1-hydroxybenzotriazole (123 mg), WSC-HC1 (175 mg) and morpholine (79 mg) at room temperature. After stirring at room temperature for 2.5 hours, the solution was poured into a mixture of water and ethyl acetate, and adjusted to pH 7.0 with aqueous sodium hydrogen carbonate. The separated organic layer was washed with saturated sodium chloride solution (x3), dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (eluent: ethyl acetate / n-hexane) to give 7β-2- (phenylacetamido) -3- (4-morpholinocarbonylmethylthiazol-2-yl) thio- 3 -ace. fem- 4-benzhydryl oxalate (147 mg). NMR (DMSO-de, d): 3.4-3.6 (10 H, m), 3.48 and 3.76 (2 H, ABq, J = 17.3 Hz), 3.87 (2 H, s), 5.25 (1 H, d, J = 5.0 Hz), 5.81 (1 H, dd, J = 5.0 and 8.5 Hz), 6.97 (1 H, s), 7.2-7.5 (15 H, m), 7.57 (1 H, s), 9.23 (1 H , d, J = * • 8.5 Hz).

Example 93 To a solution of 7β-2- (phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3-cephem-4-carboxylate benzhydryl (500 mg) in dichloromethane (10 ml) and N, N-dimethylformamide (10 mL) was added 1-hydroxy-benzotriazole (123 mg), SC-HC1 (175 mg) and 2-aminomethylpyridine (99 mg) at room temperature. After stirring at room temperature for 3 hours, the solution was poured into a mixture of water and ethyl acetate, and adjusted to pH 7.0 c with aqueous sodium hydrogen carbonate. The separated organic layer was washed with saturated sodium chloride solution (x3), dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue, and the resulting crystals were collected by filtration to give 7β- (2-phenyl-acetamido) -3- [4- (N- (2-pyridylmethyl) carbamoylmethyl) thiazol-2-yl] thio -3-cephem-4-carboxylate benzhydryl (178 mg). NMR (DMSO-de, d): 3.53 (2 H, d, J = 3.8 Hz), 3.54 and 3.78 (2 H, ABq, J = 17.5 Hz), 3.72 (2 H, s), 4.39 (2 H, d, J = 5.9 Hz), 5.23 (1 H, d, J = 5.0 Hz), 5.81 (1 H, dd, J = 5.0 and 8.4 Hz), 6.94 (1 H, s), 7.2-7.5 (17 H, m), 7.61 (1 H, s), 7.71 (1 H, dt, J = 1.8 and 7.7 Hz), 8.48 (1 H, d, J = 4.0 Hz9, 8.67 (1 H, t, J = 6.0 Hz), 9.26 (1 H, d, J = 8.4 Hz).

Example 94 To a mixture of benzhydryl 7β- (2-phenylacetamido) -3- [5-aminothiazol-2-yl) thio-3-cephem-4-carboxylate (1.47 g) and dichloromethane (4.41 ml) were added trifluoroacetic acid (2.94 ml) and anisole (1.47 ml) under ice cooling. After stirring at room temperature for 1 hour, the solution was poured into diisopropyl ether. The resulting precipitate was collected by filtration, added to a mixture of tetrahydrofuran, ethyl acetate and water, and adjusted to pH 7.2 with aqueous sodium hydrogen carbonate. The separated aqueous layer was washed with ethyl acetate, adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on HP-20 (eluent: 20% isopropanol-water). The object fraction was evaporated under reduced pressure. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 2.8 with 1 N hydrochloric acid. The extracted ethyl acetate solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure.

Ethyl acetate was added to the residue, and the resulting crystals were collected by filtration to give 7β- (2-phenylacetamido) -3- (5-aminot-iazol-2-yl) thio-3- "cephem-4-carboxylic acid. (194 mg) IR (KBr): 1774, 1678, 1656, 1515 cm "1 NMR (DMSO-de, d): 3.41 (2 H, s), 3.51 (2 H, d, J = 3.8 Hz), 5.13 (1 H, d, J = 4.7 Hz), 5.62 (1 H, dd, J = 4.7 and 8.3 Hz), 6.84 (1 H, s), 7.1-7.4 (7 H, m), 9.09 (1 H , d, J = 8.3 Hz). FAB-MASS (m / z): 449 (M + H) +.

Example 95 To a solution of 4-carboxymethyl-2-mercapto-4,5,6,7-tetrahydrobenzothiazole (780 mg) in tetrahydrofuran (11.7 ml) and dimethoxyethane (11.7 ml) was added potassium t-butoxide (667). mg) at -10 ° C, and the solution was stirred at the same temperature for 20 minutes. On the other hand, a solution of benzhydryl 7β- (2-phenylacetamido) -3-methanesulfonyloxy-3-cephem-4-carboxylate (1.64 g) in tetrahydrofuran (8.2 ml) and dimethoxyethane (8.2 ml) was added to the above solution at -15 ° C.

After stirring under ice cooling for 2 hours, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure to give the potassium salt of 7β- (2-phenylacetamido) -3- (4-carboxymethyl-4, 5, 6, 7-tetrahydrobenzothiazol-2-yl-] thio-3-cephem-4-carboxylic acid benzhydryl ester (2.02 g). NMR (DMSO-de, d): 1.4-2.1 (4 H, m), 2.1- 2.5 (1 H, m), 2.6-2.8 (2 H, m), 2.8-3.0 (1 H, m), 3.0-3.3 (1 H, m), 3.4-3.8 (4 H, m), 5.1- 5.4 (1 H, m), 5.7-5.9 (1 H, m), 6.8-7.0 (1 H,), 7.1-7.5 (15 H, m), 9.2-9.3 (1 H, m) FAB-MASS (m / z): 750 (M + H) +.

Example 96 To a solution of 4- (2-carboxyethyl) -2-mercaptothiazole (972 mg) in tetrahydrofuran (14.6 ml) and dimethoxyethane (14.6 ml) was added potassium t-butoxide (960 mg) at -10 ° C, and the mixture was stirred at the same temperature for 20 minutes. On the other hand, a solution of benzhydryl 7β- [2- (3-thienyl) acetamido] -3-methanesulfonyloxy-3-cephem-4-carboxylato (2.5 g) in tetrahydrofuran (35 g) was added to the mixture above. ml) at -15 ° C. After stirring under ice-cooling for 2 hours, the solution was poured into a mixture of water and ethyl acetate. The separated organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Diisopropyl ether was added to the residue, and the resulting precipitate was collected by filtration, to give the potassium salt of 7β- [2- (3-thienyl) acetamido] -3- [4- (2-carboxyethyl) thiazole-2- il] -thio-3-cephem-4-carboxylic acid benzhydryl (2.69 g). NMR (DMSO-de, d): 2.61 (2 H, t, J = 7.7 Hz), 2.89 (2 H, t, J = 7.8 Hz), 3.57 (2 H, s), 3.50 and 3.77 (2 H, ABq, J = 17.7 Hz), 5.27 (1 H, d, J = 4.9 Hz), 5.82 (1 H, dd, J = 4.9 and 7.7 Hz), 6.97 (1 H, s), 7.1-7.6 (14 H , m), 9.21 (1 H, d, J = 7.7 Hz). FAB-MASS (m / z): 716 (M + H) +.

Example 97 To a solution of benzhydryl 7β-amino-3- [(Z) -2- (3-pyridyl) vinyl thio] -3-cephem-4-carboxylate (500 mg) in tetrahydrofuran (12.5 ml) was added N -trimethylsilylacetamide (550 mg), and stirred at room temperature for 20 minutes. To the solution was added dropwise a solution of phenylacetyl chloride (146 μl) at -20 ° C for 2 minutes. The mixture was stirred at -20 ° - -15 ° C for 50 minutes. To the reaction mixture was added water (50 ml), ethyl acetate (50 ml) and tetrahydrofuran (15 ml). The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β- (2-phenylacetamido) -3 - [(Z) -2- (3-pyridyl) vinyl thio] -3-cephem-4-carboxylic acid benzhydryl ester (532 mg). NMR (DMSO-d6, d): 3.50 and 3.59 (2 H, ABq, J = 14 Hz), 3.82 and 4.10 (2 H, ABq, J = 18 Hz), 5.21 (1 H, d, J = 5 Hz), 5.78 (1 H, dd, J = 5 and 8 Hz), 6.76 (1 H, d, J = 11 Hz), 6.81 (1 H, d, J = 11 Hz), 6.94 (1 H, s), 7.2-7.5 (16 H, m), 7.7-7.8 (1 H, m), 8.4-8.5 (1 H, m), 8.59 (1 H, m), 9.22 (1 H, d, J = 8 Hz). APCI-MASS (m / z): 620 (M +).

Example 98 To a solution of 7β-amino-3- (E) -2- (4-pyrazolyl) vinylthio] -3-cephem-4-carboxylic acid benz-hydride (515 mg) in tetrahydrofuran (12.5 ml) was added N-trimethylsilylacetamide (550 mg), and stirred at room temperature for 15 minutes. To the solution was added dropwise a solution of phenylacetyl chloride (146 μl) at -20 ° C for 2 minutes. The mixture was stirred at -20 ° - -15 ° C for 1 hour. Water (100 ml) and ethyl acetate (100 ml) were added to the reaction mixture. The organic layer was separated, washed with a buffer solution (pH 7) and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (eluent: dichloromethane: ethyl acetate = 9: 1) to give 7β- (2-phenylacetamido) -3- [(E) -2- (1-benzylcarbonyl-pyrazole -4-yl) vinylthio] -3-cephem-4-carboxylic acid benzhydryl (93.4 mg). NMR (DMSO-de, d): 3.51 and 3.60 (2 H, ABq, J = 14 Hz), 3.80 and 3.99 (2 H, ABq, J = 18 Hz), 4.45 (2 H, s), 5.21 (1 H, d, J = 5 Hz), 5.72 (1 H, dd, J = 5 and 8 Hz), 6.74 (1 H, d, J = 15 Hz), 6.90 (1 H, s), 7.18 (1 H , d, J = 15 Hz), 7.2-7.6 (15 H, m), 8.20 (1 H, s), 8.55 (1 H, s), 9.19 (1 H, d, J = 8 Hz). APCI-MASS (m / z): 609 (M +).

Example 99 To a solution of benzhydryl 7β- (2-phenylacetamido) -3-trifluoromethanesulfonyl-3-cephem-4-carboxylate (2.0 g) in a mixture of tetrahydrofuran (20 ml), dimethoxyethane (20 ml) and N, N-dimethylformamide (20 ml) was added dipotassium salt of l-carboxymethyl-5-mercapto-1,2,3,4-tetrazole (608 mg) with stirring at -25 ° C. The mixture was stirred at -25 - -15 ° C for 30 minutes, and -15 - -8 ° C for 2 hours. To a mixture of ethyl acetate (100 ml) and ice-water (100 ml) was added the reaction mixture with stirring. To the separated aqueous solution was added ethyl acetate (150 ml). The mixture was adjusted to pH 1.8 with 1N hydrochloric acid. The organic layer was separated, washed successively with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was triturated with isopropyl ether to give 7β- (2-phenylacetamido) -3- (1-carboxymethyl-1,2,4,4-tetrazol-5-yl) thio-3-cephem-4-carboxylic acid benzhydryl ester ( 412 mg). NMR (DMSO-de, d): 3.3-3.7 (4 H, m), 5.2-5.5 (2 H, m), 5.24 (1 H, d, J = 5 Hz), 5.83 (1 H, dd, J = 5 and 8 Hz), 6.95 (1 H, s), 7.2-7.5 (15 H, m), 9.19 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 643.1.

Example 100 To a solution of benzhydryl 7β- (2-phenylacetamido) -3- [2- (3-pyridyl) ethylthio] -3-cephem-4-carboxylate (632 mg) in a mixture of dichloromethane (1.8 ml) and anisole (0.6 ml) was added trifluoroacetic acid (1.2 ml) under ice cooling. The mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was poured into diisopropyl ether (60 ml), and the resulting precipitate was collected by filtration and dried in vacuo. The precipitate was dissolved in a mixture of aqueous sodium hydrogen carbonate (188 mg / 50 ml), tetrahydrofuran (20 ml) and ethyl acetate (40 ml). To the separated aqueous layer was added tetrahydrofuran (20 ml) and ethyl acetate (40 ml), and adjusted to pH 3.0 with 1-N hydrochloric acid. The resulting precipitate was collected by filtration, washed with water, ethyl acetate and n-hexane, and dried to give 7β- (2-phenylacetamido) -3- [2- (3-pyridyl) ethylthio] -3 acid. -cephem-4-carboxylic acid (366 mg). NMR (DMSO-de, d): 2.7-2.9 (2 H, m), 3.0-3.2 (2 H, m), 3.49 and 3.58 (2 H, ABq, J = 14 Hz), 3.75 and 3.85 (2 H) , ABq, J = 17 Hz), 5.11 (1 H, d, J = 5 Hz), 5.62 (1 H, d, J = 5 and 8 Hz), 7.2-7.4 (6 H, m), 7.6-7.8 (1 H, m), 8.4-8.5 (2 H, m), 9.13 (1 H, d, J = 8 Hz). FAB-MASS (m / z): 456.0.

Example 101 To a solution of benzhydryl 7β- (2-phenylacetamido) -3- [4- (carbamoylmethylthiazol-2-yl) thiomethylthio] -3-cephem-4-carboxylate (125 mg) in a mixture of dichloromethane (0.4 ml) ) and anisole (0.125 ml) was added trifluoroacetic acid (0.25 ml) under ice cooling. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into diisopropyl ether (50 ml), and the resulting precipitate was collected by filtration to give 7β- (2-phenylacetamido) -3- [4- (carbamoylmethylthiazol-2-yl) thio-methylthio] -3-cephem-4-carboxylic acid (89.0 mg). NMR (DMSO-de, d): 3.4-3.6 (6 H, m), 3.40 and 3.76- (2 H, ABq, J = 18 Hz), 5.20 (1 H, d, J = 5 Hz), 5.74 ( 1 H, dd, J = 5 and 8 Hz), 6.99 (1 H, sa), 7.1-7.3 (5 H, m), 7.44 (1 H, sa), 7.53 (1 H, s), 9.22 (1 H, d, J == 8 Hz).

Example 102 To a suspension of 7β- (2-phenyl-acetamido) -3- [4- (carbamoylmethylthiazol-2-yl) thio] -3-cephem-4-carboxylic acid (1.84 g), water (18 ml) and Acetone (10 ml) was added sodium acetate (924 mg) and dissolved. The solution was stirred for 1 hour at room temperature. The resulting precipitate was collected by filtration, washed with acetone, and dried in vacuo to give 7β- (2-phenylacetamido) -3- [4- (carbamoylmethyl-thiazol-2-yl) thio] -3-cephem-4 sodium carboxylate (890 mg). IR (Nujol): 3250, 1750, 1650, 1605, 1530, 1350, 1260 cm "1 NMR (D20 d): 3.40 and 3.76 (2 H, ABq, J = 17 Hz), 3.6-3.8 (4 H,) , 5.19 (1 H, d, J = 5 Hz), 5.68 (1 H, d, J = 5 Hz), 7.3-7.5 (6 H, m) FAB-MASS (m / z): 512.6.

Example 103 To a solution of 7β- (2-phenylacetamido) -3- [4- (carboxylmethylthiazol-2-yl) thio] -3-cephem-4-carbo-xylic acid (950 mg) in tetrahydrofuran (37 ml) and methanol (20 ml) was added a solution of sodium acetate (317 mg) in methanol (20 ml). The mixture was stirred at room temperature for 20 minutes. The resulting precipitate was collected by filtration, washed successively with methanol and n-hexane, dried in vacuo to give 7β- (2-phenylacetamido) -3- [4- (carboxylmethyl-thiazol-2-yl) thio] -3 -cephem-4-carboxylate sodium (0.77 g). IR (KBr): 3400, 3330, 1770, 1710, 1650, 1600, 1580, 1530, 1390, 1350, 1260, 1220 cm "1 NMR (DMSO-de, d): 3.42 and 3.75 (2 H, ABq, J = 18 Hz), 3.6-3.8 (4 H, m), 5.19 (1 H, d, J = 5 Hz), 5.67 (1 H, d, J = 5 Hz), 7.3-7.5 (6 H, m) FAB-MASS (m / z): 535.9.

Example 104 To a solution of 2-mercapto-5-methyl-1,3,4-thiadiazole (142 mg) in dimethoxyethane (3 ml) was added potassium t-butoxide (120 mg) at -20 ° C with stirring, and the mixture was stirred at -20 - -10 ° C for 30 minutes to give the potassium salt solution. On the other hand, to a suspension of 7β- (2-phenylacetamido) -3-trifluoromethanesulfonyloxy-3-cephem-4-carboxylic acid (500 mg) in dimethoxyethane (4 ml) and dichloromethane (7.5 ml) was added N-trimethylsilylacetamide (562 mg). The suspension was stirred at room temperature for 30 minutes. To the mixture was added the solution of the potassium salt prepared above at -20 ° C, and the mixture was stirred at -20 - 10 ° C for 30 minutes, and at 0 - 5 ° C for 1.5 hours. The mixture was poured into a mixture of ice-water (20 ml) and ethyl acetate (30 ml). The organic layer was separated, and water (20 ml) was added. The mixture was adjusted to pH 6.8 with 1N sodium hydroxide solution. The aqueous layer was separated, and evaporated in vacuo to remove the organic solvent. The resulting residue was purified by high pressure liquid chromatography (CLAP) (R-ODS-C-15, YMC packing) eluting with 27% acetonitrile-phosphate buffer (pH 3. 0). The solution was extracted with ethyl acetate (100 ml). The extract was concentrated in vacuo. The residue was dissolved in acetonitrile (60 ml) and water (20 ml). The solution was concentrated in vacuo. The residue was triturated with water to give 7β- (2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid (262 mg).

NMR (DMSO-de, d): 2.72 (3 H, s), 3.48 and 3.57 (2 H, ABq, J = 14 Hz), 3.53 and 3.85 (2 H, ABq, J = 18 Hz), 5.21 (1 H, d, J = 5 Hz), 5.78 (1 H, dd, J = 5 and 8 Hz), 7-, 2-7.4 (5 H, m), 9.23 (1 H, d, J = 8 Hz) .

Example 105 To a solution of 7β- (2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio] -3-cephem-4-carboxylic acid (492 mg) in N, N-dimethylacetamide (4 ml) was added cesium carbonate (200 mg) under ice cooling, and stirred at the same temperature for 1.5 hours. To the mixture was added iodomethyl pivalate (297 mg), stirred for 1 hour at the same temperature. Water (50 ml) and ethyl acetate (50 ml) were added to the mixture. The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether pair 7β- (2-phenylacetamido) -3- (5-methyl, 3,4-thiadiazol-2-yl) thio] -3-cephem-4-carboxy pivaloyloxymethyl ester (492 mg ). NMR (CDC13, d): 1.21 (9 H, s), 2.78 (3 H, s), 3.46 and 3.75 (2 H, ABq, J = 18 Hz), 3.60 and 3.69 (2 H, ABq, J = 16 Hz), 5.01 (1 H, d, J = 5 Hz), 5.8-6.0 (3 H, m), 6.12 (1 H, d, J = 9 Hz), 7.2-7.4 (5 H, m). FAB-MASS (m / z): 563.0.

Example 106 To a solution of 7β- [2- (2-aminothiazol-4-yl) acetamido] -3- (5-met il-1,3,4-thiadiazol-2-yl) thio-3-cephem-4 Benzhydryl carboxylate (1.0 g) in a mixture of tetrahydrofuran (15 ml) and N, N-dimethylformamide (5 ml) was added acetyl chloride (245 μl) and pyridine (254 μl) under ice cooling. The mixture was stirred at the same temperature for 4 hours. The reaction mixture was added to a mixture of ethyl acetate (70 ml) and ice-water (50 ml). The organic layer was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β- [2- (2-acetyl-aminothiazol-4-yl) acetamido] -3- (5-methyl-1-, 3,4-thiadiazol-2-yl) thio- Benzhydryl 3-cephem-4-carboxylate (675 mg). NMR (DMSO-de, d): 2.11 (3 H, s), 2.71 (3 H, s), 3.58 and 3.87 (2 H, ABq, J = 17 Hz), 3.59 (2 H, s), 5.28 ( 1 H, d, J = 5 Hz), 5.87 (1 H, dd, J = 5 and 8 Hz), 6.87 (1 H, s), 6.97 (1 H, s), 7.2-7.4 (10 H, m ), 9.14 (1 H, d, J = 8 Hz), 12.09 (1 H, s). FAB-MASS (m / z): 679.1.

Example 107 To a suspension of 7β- [2- (5-chloro-2-formylaminothiazol-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thio- 3-cephem-4-carboxylic acid (380 mg), methanol (4 ml) and tetrahydrofuran (4 ml) were added concentrated hydrochloric acid (153 μl). The mixture was stirred for 5 hours at 35 ° C. The reaction mixture was added to a mixture of ethyl acetate (20 ml) and ice-water (50 ml). To the aqueous solution was added ethyl acetate (20 ml). The mixture was adjusted to pH 7 with 1 N sodium hydroxide solution. To the separated aqueous solution was added ethyl acetate (20 ml). The mixture was adjusted to pH 2 with 1N hydrochloric acid. The precipitate was collected by filtration, washed with ethyl acetate, and settled to give 7β- [2- (2-amino-5-chlorothiazol-4-yl) acid. acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-yl) thio-3-cephem-4-carboxylic acid (188 mg). NMR (DMSO-de, d): 2.72 (3 H, s), 3.38 (2 H, s), 3.53 and 3.85 (2 H, ABq, J = 18 Hz), 5.23 (1 H, d, J = 5 Hz), 5.78 (1 H, dd, J = 5 and 8 Hz), 7.16 (2 H, sa), 9.06 (1 H, d, J = 8 Hz).

Example 108 To a solution of 4- (2-mercaptothiazol-4-yl) benzoic acid in tetrahydrofuran (13.7 ml) and dimethoxyethane (13.7 ml) was added potassium t-butoxide (642 mg) at -10 ° C, and the solution was stirred at the same temperature for 20 minutes. On the other hand, a solution of 7β- (2-phenylacetamido] -3-methanesulfonyloxy-3-cephem-4-carboxylate benzhydryl (1.8 g) in tetrahydrofuran (20 ml) was added to the above solution at -15 ° C. After stirring under ice cooling for 2.5 hours, the solution was poured into a mixture of water (70 ml) and ethyl acetate (70 ml), and adjusted to pH 7.0 with 1 N hydrochloric acid. The separated organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel, and eluted with a mixture of ethyl acetate and methanol (4.5: 1). The fractions containing the subject compound were combined and evaporated in vacuo to give the potassium salt of 7β- (2-phenylacetamido) -3- [4- (4-carboxyphenyl) thiazol-2-yl] -thio-3- Benzhydryl cefem-4-carboxylate (465 mg). IR (KBr): 1787, 1739, 1685, 1409, 1375, 1224 cm ": NMR (DMSO-de, d): 3.56 (2 H, sa), 3.68 and 3.92 (2 H, ABq, J = 17.7 Hz) , 5.30 (1 H, d, J = 5.0 Hz), 5.86 (1 H, dd, J = 5.0 and 8.3 Hz), 6.98 (1 H, s), 7.15-7.50 (15 H, m), 7.85-8.15 (4 H, m), 8.30 (1 H, s), 9.28 (1 H, d, J = 8.3 Hz).

"Example 109 To a mixture of potassium salt of 7β- (2-phenylacetamido) -3- [4- (4-carboxyphenyl) thiazol-2-yl] -thio-3-cephem-4-carboxylic acid benzhydryl (450 mg), anisole (0.45 ml) and dichloromethane (1.35 ml) was added -0-trifluoroacetic acid (0.9 ml) at 15 ° C. After stirring at room temperature for 1.5 hours, the solution was poured into diisopropyl ether. was collected by filtration, it was added to a mixture of tetrahydrofuran (10 ml) and water (15 ml), and solution 5 was adjusted to pH 7.2 with sodium hydrogen carbonate and charged. The separated aqueous solution was adjusted to pH 3.0 with 1N hydrochloric acid, and extracted with tetrahydrofuran. The tetrahydrofuran solution was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. Ethyl acetate was added to the residue, and the resulting powder was collected by filtration and dried in vacuo to yield 7β- (2-phenylacetamido) -3- [4- (4-carboxyphenyl) thiazol-2-yl] -thio acid. - 3-cephem-4-carboxylic acid 5 (75 mg).

IR (KBr): 1776, 1685, 1660, 1610, 1351, 1247 cm "1 NMR (DMSO-de, d): 3.53 (2 H, dd, J = 13.9 and 18.6 Hz), 3.62 and 3.90 (2 H, ABq, J = 17.7 Hz), 5.26 (1 H, d, J = 5.0 Hz), 5.77 (1 H, dd, J = 5.0 and 8.3 Hz), 7.15-7.35 (5 H, m), 8.04 (4 H , dd, J = 8.7 and 13.3 Hz), 8.40 (1 H, s), 9.23 (1 H, d, J = 8.3 Hz), FAB-MASS (m / z): 554 (M + H) +.

The following compound was obtained according to a manner similar to that of Example 103.

Example 110 7β- [2- (2-thienyl) acetamido) -3- [4- (2-carboxyethyl) thiazol-2-yl] thio-3-cephem-4-carboxylate sodium IR (KBr): 1778, 1658 , 1527, 1388, 1249 cm "1 NMR (DMSO-de, d): 2.50-2.65 (2 H, m), 2.80-2.95 (2 H, m), 3.26 and 3.70 (2 H, ABq, J = 16.8 Hz), 3.76 (2 H, s), 5.08 (1 H, d, J = 4.97 Hz), 5.56 (1 H, dd, J = 5.0 and 8.4 Hz), 6.85-7.00 (2 H, m), 7.24 (1 H, s), 7.30-7.40 (1 H, m), 9.17 (1 H > d, J = 8.4 Hz).

Example 111 To a solution of 7β- [2- (2-thienyl) ethenamido] -3- [4- (2-carboxyethyl) thiazol-2-yl] -thio-3-cephem-4-carboxylic acid (100 mg) in water (50 ml) was added 0.1 mol / l sodium hydroxide solution (3.9 ml). The solution was lyophilized to give 7β- [2- (2-thienyl) acetamido] -3- [4- (2-carboxyethyl) thiazol-2-yl] -thio-3-cephem-4-carboxylate disodium (108.3 mg ). IR (KBr): 1766, 1662, 1612, 1552, 1348, 1238 cm "1 NMR (DMSO-de, d): 2.10-2.30 (2 H, m), 2.70-2.90 (2 H, m), 3.27 and 3.70 (2 H, ABq, J = 16.8 Hz), 3.76 (2 H, s), . 08 (1 H, d, J = 5.0 Hz), 5.56 (1 H, dd, J = 5.0 and 8.4) Hz), 6.90-7.0 (2 H, m), 7.15 (1 H, s), 7.30-7.40 (1 H, m), 9.20 (1 H, d, J = 8.4 Hz). FAB-MASS (m / z): 534 (M + H) +.

Example 112 To a solution of 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) thio-3-cephem-4-carboxylic acid (100 mg) in water (50 ml) was added hydroxide solution of 0.1 mol / l sodium (4.06 ml). The solution was lyophilized. The powder obtained above was dissolved in a mixture of methanol (0.5 ml) and acetone (1.3 ml) under stirring at 30 ° C. Stirring was continued for 2 hours at room temperature to give crystals, which were collected by filtration and dried to give 7β- (2-phenylacetamido) -3- (4-carboxymethylthiazol-2-yl) -thio-3-cephem-4-carboxylate disodium (69.1 mg) IR (KBr): 1753, 1656, 1623, 1535, 1390, 1261 cm "1 NMR (DMSO-de, d): 3.25 and 3.71 (2 H, ABq, J = 17.0 Hz), 3. 53 (2 H, dd, J = 14 and 17.0 Hz), 3.65 (2 H, s), 5.05 (1 H, d, J = 5.0 Hz), 5.54 (1 H, dd, J = 5.0 and 8.4 Hz), 7. 05-7.35 (5 H, m), 7.37 (1 H, s), 9.15 (1 H, d, J = 8.4 Hz). FAB-MASS (m / z): 536 (M + H) +.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, property is claimed as contained in the following:

Claims

RE IVINDICATIONS

1. A cephem compound of the following general formula (I): characterized in that: R1 is aryl (lower alkyl), which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl which can form a ring together with the carbon atom to which the lower alkyl, hydroxy and halogen are attached; heterocyclyl (lower alkyl) which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and protected amino; or cyano (lower alkenylthio) (lower alkyl); R2 is a heterocyclic group which has 1 to 3 suitable substituent (s) selected from the group consisting of acyl (lower alkyl), hydroxy- (lower alkyl), mono or di (lower alkylamino) - (lower alkyl), amino (lower alkyl), protected amino (lower alkyl), 5-acyl, acylamino and aryl having carboxy, in which the heterocyclic group may additionally have lower alkyl; pyridyl (lower alkyl); pyrazolylethyl, which may have aryl (lower alkyl * 0); thiadiazolyl (lower alkyl); 5-ami otiazolyl; thiadiazolyl having lower alkyl; heterocyclyl (lower alkenyl) which may have from 1 to 3 suitable substituent (s); or heterocyclicthio (lower alkyl) which may have from 1 to 3 suitable substituent (s); and R3 is carboxy or protected carboxy, provided that 0 1) when R1 is aryl (lower alkyl) and R2 is thiadiazolyl having lower alkyl, then R3 is acyloxy (lower alkoxycarbonyl), 2) when R1 is aryl (alkyl) lower) having halogen, then R2 is not thiadiazolyl having lower alkyl, when R1 is aminothiazolyl (lower alkyl) then R ~ is not thiadiazolyl having lower alkyl.

2. A compound according to claim 1, characterized in that: R1 is phenyl (lower alkyl), which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, which it can form a ring of 3 to β members together with the carbon atom to which the lower alkyl, hydroxy and halogen are attached; -thienyl (lower alkyl), thiazolyl (lower alkyl) or thiadiazolyl (lower alkyl), each of which may have from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkenyl, lower alkylidene, halogen, amino and acylamino; o-cyano (lower alkenylthio) (lower alkyl); R2 is thiazolyl, which has from 1 to 3 suitable substituent (s) selected from the group consisting of acyl (lower alkyl), hydroxy (lower alkyl), acyl, acylamino and phenyl having carboxy, wherein the thiazolyl may additionally have a lower alkyl; -thiadiazolyl, which has from 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, hydroxy (lower alkyl), mono or di (lower alkylamino) (lower alkyl) amino (alkyl) lower), acylamino (lower alkyl) and acyl (lower alkyl); 4, 5, 6, 7-tetrahydrobenzothiazolyl, which has acyl (lower alkyl); -pyridyl (lower alkyl); -pyrazolylethyl, which may have triphenyl (lower alkyl); -thiadiazolyl (lower alkyl); -5-aminothiazolyl; -triazolyl, which has acyl (lower alkyl); -tetrazolyl, which has acyl (lower alkyl); pyridyl (lower alkenyl); -pyrazolyl (lower alkenyl), which may have acyl; or -thiazolyl (lower alkylthio), which may have acyl (lower alkyl), R3 is carboxy or carboxy protected; with the proviso that 1) when R1 is phenyl (lower alkyl) and R2 is thiadiazolyl having lower alkyl, then R3 is acyloxy (lower alkoxycarbonyl), 2) when R1 is phenyl (lower alkyl) having - halogen, then R2 it is not thiadiazolyl having lower alkyl, 3) when R 1 is aminothiazolyl (lower alkyl), then R 2 is not thiadiazolyl having lower alkyl.

3. A compound according to claim 2, characterized in that: R1 is phenyl (lower alkyl), or thienyl (lower alkyl), R2 is thiazolyl, which has carboxy (lower alkyl), thiazolyl having carbamoyl (lower alkyl), or thiazolyl having N, N-di (lower alkylcarbamoyl) (lower alkyl), and R3 is carboxy.

4. A compound according to claim 3, characterized in that: R1 is phenyl (lower alkyl), R2 is thiazolyl, which has carboxy (lower alkyl), and R3 is carboxy.

5. A compound according to claim 3, characterized in that: R1 is phenyl (lower alkyl), R2 is thiazolyl, which has carbamoyl (lower alkyl), and R3 is carboxy.

6. A compound according to claim 3, characterized in that: R1 is thienyl (lower alkyl), R2 is thiazolyl, which has carboxy (lower alkyl) o or thiazolyl having carbamoyl (lower alkyl), and R3 is carboxy.

7. A compound according to claim 4, characterized in that it is: 7β- (2-phenylacetamido) -3- (4-carboxymethyl thiazolyl) -thio] -3-cephem-4-carboxylic acid.

8. A compound according to claim 5, characterized in that it is: 7β- (2-phenylacetamido) -3- (4-carbamoylmethyl-1-thiazolyl) thio] -3-cephem-4-carboxylic acid.

9. A compound according to claim 3, characterized in that it is: 7β- [2- (3-thienyl) acetamido) -3- (4-carboxymethylthiazolyl) thio] -3-cephem-4-carboxylic acid, 7β- [2 - (2-thienyl) acetamido) -3- (4-carboxyethyl) thiazolyl) thio] -3-cephem-4-carboxylic acid, or 7β- [2- (3-thienyl) acetamido) -3- (4-carbamoylmethi) acid -thiazolyl) thio] -3-cephem-4-carboxylic acid.

10. A process for preparing a compound according to claim 1, or a salt thereof, characterized in that it comprises: (i) reacting a compound of the formula (II): wherein R1 and R3 are each as defined in claim 1, and R4 is a leaving group, or a salt thereof, with a compound of the formula (III): HS-R "(III) wherein R2 was defined in claim 1, or a salt thereof, or (ii) subjecting a compound of the formula (la): wherein R1 and R2 are each as defined in claim 1, and R5 is protected carboxy, or a salt thereof, at a removal reaction of the carboxy protecting group, to give a compound of the formula (Ib): wherein R1 and R2 are each as defined in claim 1, or a salt thereof, or (iii) reacting a compound of the formula (IV): wherein R2 and R2 are each as defined in claim 1, or the reactive derivative thereof in the amino group or a salt thereof, with a compound of the formula (V): R -COOH; v) wherein R1 was defined in claim 1, or its reactive derivative in the carboxy group or a salt thereof, or (iv) subjecting a compound of the formula (Ib): wherein R1 and R2 are each as defined in claim 1, or their reactive derivative in the carboxy group or a salt thereof, to a carboxy protection reaction, to give a compound of the formula (Ia): wherein R1 and R2 are each as defined in claim 1, and R5 is as defined above, or a salt thereof.

11. A pharmaceutical composition characterized in that it comprises, as an active ingredient, a compound according to claim 1 or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable carriers or excipients.

12. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is for the manufacture of a medicament.

13. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that it is to be used as a medicament.

14. A method for the prophylactic and / or therapeutic treatment of diseases caused by Helicobacter pylori infection, characterized in that it comprises administering a cephem compound according to claim 1 or a pharmaceutically acceptable salt thereof to a human or animal. * n

15. A product comprising the cephem compound (I) according to claim 1 or a pharmaceutically acceptable salt thereof and an acid secretion inhibitor as a combined preparation, characterized in that it is for simultaneous, separate or sequential for the prevention and / or treatment of diseases caused by Helicobacter pylori infection.

16. The cephem compound (I) according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that it is for the adjuvant therapy of diseases caused by infection with Helicobacter pylori, with an acid secretion inhibitor. .

17. Use of the cephem compound (I) according to claim 1 or a pharmaceutically acceptable salt thereof and an acid secretion inhibitor, characterized in that it is for the manufacture of a medicament for simultaneous, separate or sequential use for the prevention and / or treatment of diseases caused by infection with Helicobacter pylori.

18. A product comprising the cephem compound (I) according to claim 1 and an acid secretion inhibitor, characterized in that it is for simultaneous, separate or sequential use as a medicament.

19. A pharmaceutical composition, characterized in that it comprises the cephem compound (I) according to claim 1, and an inhibitor of acid secretion, and optionally pharmaceutically acceptable carriers or excipients.

20. A product, characterized in that it comprises: a) the cephem compound (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and b) an acid secretion inhibitor, in a weight ratio of: a) ab) from 0.01 / 1 to 100/1.

21. A method for the treatment or inhibition of diseases caused by infection by Helicobacter pylori, characterized in that it comprises administering an effective amount of the cephem compound (I) according to claim 1 to a patient in need of such treatment or inhibition.

22. The method according to claim 21, characterized in that the cephem (I) compound according to claim 1 is administered to the patient in combination with an acid secretion inhibitor in a weight ratio of the cephem (I) compound of according to claim 1 to an acid secretion inhibitor in the range from 0.01 / 1 to 100/1.